rs756908183

Positions:

chr4-186274190-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000128.4(F11):c.400C>T(p.Gln134Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,042 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

F11
NM_000128.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 1.33

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 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-186274190-C-T is Pathogenic according to our data. Variant chr4-186274190-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188913.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F11	NM_000128.4 linkuse as main transcript	c.400C>T	p.Gln134Ter	stop_gained	5/15	ENST00000403665.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F11	ENST00000403665.7 linkuse as main transcript	c.400C>T	p.Gln134Ter	stop_gained	5/15	1	NM_000128.4	P1	P03951-1
F11	ENST00000492972.6 linkuse as main transcript	c.400C>T	p.Gln134Ter	stop_gained	5/5	2
F11	ENST00000514715.1 linkuse as main transcript	n.272C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152156

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251280

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000829

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188913). This variant is also known as Gln116X. This premature translational stop signal has been observed in individual(s) with autosomal recessive severe factor XI deficiency (PMID: 16519703, 18515884). This variant is present in population databases (rs756908183, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gln134*) in the F11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in F11 are known to be pathogenic (PMID: 23929304). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in the heterozygous state in an individual with a factor XI antigen level of 43%, but who did not have spontaneous bleeding or bleeding with hemostatic challenge (Dossenbach-Glaninger et al., 2006); Identified in an individual who had minor bleeding after surgery and a factor XI antigen level of 4%, who also harbored a second variant in F11 (Castaman et al., 2008); Also known as Q116X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 10593931, 18515884, 16519703) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 26, 2016	- -

Hereditary factor XI deficiency disease

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 06, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 06, 2018	The F11 c.400C>T (p.Gln134Ter) variant, also known as p.Gln116Ter, is a stop-gained variant that is predicted to result in a premature termination of the protein. Dossenbach-Glaninger et al. (2006) identified the p.Gln134Ter variant in a heterozygous state in an Austrian probands with factor XI deficiency. The proband had approximately half the normal level of factor XI. Control data are unavailable for this variant, which is reported at a frequency of 0.000063 in the European (non-Finnish) population of the Genome Aggregation Database. Due to the potential impact of stop-gained variants and the limited evidence from the literature, the p.Gln134Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for factor XI deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Abnormal bleeding

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Plasma factor XI deficiency

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.30

MutationTaster

Benign

1.0

A;D;N

Vest4

0.84

GERP RS

3.9

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