rs748926718

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000128.4(F11):c.1103G>A(p.Gly368Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G368A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

F11
NM_000128.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

F11 (HGNC:3529): (coagulation factor XI) This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

F11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000128.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-186280547-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2734694.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 4-186280548-G-A is Pathogenic according to our data. Variant chr4-186280548-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2734695.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4 linkuse as main transcript	c.1103G>A	p.Gly368Glu	missense_variant	10/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7 linkuse as main transcript	c.1103G>A	p.Gly368Glu	missense_variant	10/15	1	NM_000128.4	P1	P03951-1
F11	ENST00000452239.1 linkuse as main transcript	c.551G>A	p.Gly184Glu	missense_variant	5/6	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251366

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt F11 protein function. Experimental studies have shown that this missense change affects F11 function (PMID: 15026311). This variant disrupts the p.Gly350 amino acid residue in F11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14717969). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Gly350Glu. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 368 of the F11 protein (p.Gly368Glu). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive factor XI deficiency (PMID: 33751533). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.4

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;.

Vest4

0.85

MutPred

0.85

Loss of sheet (P = 0.0181);.;

MVP

0.99

MPC

0.57

ClinPred

0.99

GERP RS

5.2

Varity_R

0.98

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over