rs61753266

chr13-113140972-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/19 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:4
• Conservation: PhyloP100: 0.474

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058690608).
• BP6: Variant 13-113140972-G-A is Benign according to our data. Variant chr13-113140972-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12061.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}.
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F10	NM_000504.4	c.424G>A	p.Glu142Lys	missense_variant	5/8	ENST00000375559.8
F10	NM_001312675.2	c.424G>A	p.Glu142Lys	missense_variant	5/8
F10	NM_001312674.2	c.370+1502G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F10	ENST00000375559.8	c.424G>A	p.Glu142Lys	missense_variant	5/8	1	NM_000504.4	P1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152238 Hom.: 2 Cov.: 32

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.: 4 AF XY: 0.00468 AC XY: 636 AN XY: 135880

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.: 20 Cov.: 31 AF XY: 0.00390 AC XY: 2837 AN XY: 727192

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.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74492

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.: 3

Bravo AF: 0.00185

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00449 AC: 545

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	F10: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Factor X deficiency Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1995	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Uncertain significance, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2017	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. -

Abnormal bleeding Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

F10-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2022

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	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.31	T;.;D
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.72	T;T;T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	4.4e-9	A;A;A
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs61753266; hg19: chr13-113795286; COSMIC: COSV65020911;