Factor XI Variant Database

In Depth Variant Analysis: c.325G>A (p.Ala109Thr)

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c.325G>A

p.Ala109Thr (Legacy AA No. 91)

Variant Type:

Point

Domain:

Linker

Codon Change:

G>A

Variant Effect:

Missense

No. of Patients Reported:

Phenotype:

Allele Count *:

Allele Number *:

282654

Allele Frequency *:

0.000021

Variant Comments & Reference:

Being located at the last position of exon 4, within a native donor splice site, this mutation may affect the correct splicing of the F11 mRNA. RT-PCR assays performed on total RNA demonstrated that Ala91Thr abolishes the native donor splice site causing the skipping of the affected exon, eventually resulting in a frameshift followed by a premature termination codon. This mutation is predicted to lead to the synthesis of truncated FXI proteins. Such proteins might be recognised as abnormal by cellular quality control systems, resulting in intracellular retention and protein degradation. Mitchell et al 2006, Guella et al 2008, Duncan et al 2008, Tiscia et al 2017, Esteban et al 2017, Colakoglu et al 2018

Patient Information: Show

Patient_ID	Age	Gender	Race	FXI:C%	FXI:Ag(%)	Inheritance	Other Variants	Severity	Comments	Reference
220			UK Population	9		Compound heterozygote	c.1021G>A (p.Glu341Lys)	Not Reported		Mitchell et al 2006
221			UK Population	45		Heterozygote		Not Reported		Mitchell et al 2006
222			UK Population	2		Compound heterozygote	c.438C>A (p.Cys146*)	Not Reported		Mitchell et al 2006
284		F	Italian	26	39	Heterozygote		Not Reported	Haemorrhagic episodes	Guella et al 2008
404	42	M		2		Compound heterozygote	c.365G>A (p.Gly122Asp)	Not Reported	APTT: 106 s	Duncan et al 2008
522	4	M	Turkish			Heterozygote		Not Reported	Asymptomatic	Colakoglu et al 2018
523	42	M	Turkish			Heterozygote		Not Reported	Asymptomatic	Colakoglu et al 2018
528	12	F	Italian	<1		Compound heterozygote		Not Reported	Asymptomatic	Tiscia et al 2017
529	37	M	Italian	32		Heterozygote		Not Reported	Epistaxis	Tiscia et al 2017
530	31	F	Italian	35		Heterozygote		Not Reported	Asymptomatic	Tiscia et al 2017
604	60	M	Spanish	37		Heterozygote		Not Reported		Esteban et al 2017

Residue Information:

	Name	Type	Cyclic	Size	Position	Hydrophobicity	Charge
Wild Type	Ala	aliphatic	acyclic	small	buried	hydrophobic	neutral
Mutated	Thr	-	acyclic	medium	surface	hydrophilic	neutral

Substitution Analysis:

Grantham Score : 58

PolyPhen-2 Prediction : Benign (SCORE: 0.002)

SIFT Prediction : Tolerated (SCORE: 0.18)

PROVEAN Prediction : Neutral (SCORE: -1.487)

Structural Implications:

Ala109 is a buried residue (surface accessibility value = 1 ).

Ala109 is in a random coil area of the FXI structure.

The DSSP assignment for this residue is ... C.

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