rs61753266

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000504.4(F10):c.424G>A(p.Glu142Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,142 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 20 hom. )

Consequence

F10
NM_000504.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:4

Conservation

PhyloP100: 0.474

Variant links:

Genes affected

F10 (HGNC:3528): (coagulation factor X) This gene encodes the vitamin K-dependent coagulation factor X of the blood coagulation cascade. This factor undergoes multiple processing steps before its preproprotein is converted to a mature two-chain form by the excision of the tripeptide RKR. Two chains of the factor are held together by 1 or more disulfide bonds; the light chain contains 2 EGF-like domains, while the heavy chain contains the catalytic domain which is structurally homologous to those of the other hemostatic serine proteases. The mature factor is activated by the cleavage of the activation peptide by factor IXa (in the intrisic pathway), or by factor VIIa (in the extrinsic pathway). The activated factor then converts prothrombin to thrombin in the presence of factor Va, Ca+2, and phospholipid during blood clotting. Mutations of this gene result in factor X deficiency, a hemorrhagic condition of variable severity. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing to generate mature polypeptides. [provided by RefSeq, Aug 2015]

F10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058690608).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (503/152356) while in subpopulation NFE AF= 0.00328 (223/68038). AF 95% confidence interval is 0.00292. There are 2 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F10	NM_000504.4 link	c.424G>A	p.Glu142Lys	missense_variant	Exon 5 of 8	ENST00000375559.8	NP_000495.1	P00742Q5JVE7
F10	NM_001312675.2 link	c.424G>A	p.Glu142Lys	missense_variant	Exon 5 of 8		NP_001299604.1	P00742Q5JVE8
F10	NM_001312674.2 link	c.370+1502G>A		intron_variant	Intron 4 of 6		NP_001299603.1	P00742

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F10	ENST00000375559.8 link	c.424G>A	p.Glu142Lys	missense_variant	Exon 5 of 8	1	NM_000504.4	ENSP00000364709.3		P00742

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

503

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00328

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00445

AC:

1118

AN:

251310

Hom.:

AF XY:

0.00468

AC XY:

636

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.00441

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00381

AC:

5563

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

2837

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00339

Gnomad4 FIN exome

AF:

0.0186

Gnomad4 NFE exome

AF:

0.00347

Gnomad4 OTH exome

AF:

0.00343

GnomAD4 genome

AF:

0.00330

AC:

503

AN:

152356

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0188

Gnomad4 NFE

AF:

0.00328

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.00185

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00449

AC:

545

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

F10: BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM1_supporting, PM3_strong, PS3_moderate -

Factor X deficiency

Pathogenic:1Uncertain:1

Aug 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary factor X deficiency disease

Uncertain:2

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Nov 16, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 12, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu142Lys (previously reported as Glu102Lys) variant in F10 is classified as likely benign because it has been identified in 1.8% (200/10624) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org v.3.1.2), including 2 homozygotes. This variant has been reported in individuals with factor X deficiency, but it has been found alongside other homozygous variants (Marchetti 1995 PMID: 7669671, Forberg 2000 PMID: 10739379, Bastida 2016 PMID: 26879396, Downes 2019 PMID: 31064749). In vitro functional studies show that this variant retains function similar to wild type, however, may have a slight reduction as it has not been studied in isolation. This reduction is thought to be below the clinical threshold for disease (Forberg 2000 PMID: 10739379); however, these types of assays may not accurately represent biological function. ACMG/AMP criteria applied: BS1, BS3_Supporting. -

Abnormal bleeding

Uncertain:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

F10-related disorder

Benign:1

Jan 06, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;.;D

Eigen

Benign

-0.021

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.6

.;.;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.76

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

0.99

D;D;P

Vest4

0.46

MVP

0.98

MPC

1.3

ClinPred

0.016

GERP RS

3.8

Varity_R

0.54

gMVP

0.85

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