rs149212700

Positions:

• chr13-113148922-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_Supporting

The NM_000504.4(F10):​c.872G>A​(p.Arg291Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,613,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: F10 NM_000504.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.58

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a disulfide_bond Interchain (between light and heavy chains) (size 170) in uniprot entity FA10_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000504.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012232184).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000309 (451/1461080) while in subpopulation MID AF= 0.00104 (6/5768). AF 95% confidence interval is 0.000502. There are 1 homozygotes in gnomad4_exome. There are 212 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F10	NM_000504.4	c.872G>A	p.Arg291Gln	missense_variant	8/8	ENST00000375559.8	NP_000495.1
F10	NM_001312674.2	c.740G>A	p.Arg247Gln	missense_variant	7/7		NP_001299603.1
F10	NM_001312675.2	c.862G>A	p.Gly288Arg	missense_variant	8/8		NP_001299604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F10	ENST00000375559.8	c.872G>A	p.Arg291Gln	missense_variant	8/8	1	NM_000504.4	ENSP00000364709.3
F10	ENST00000375551.7	c.862G>A	p.Gly288Arg	missense_variant	8/8	1		ENSP00000364701.3
F10	ENST00000409306.5	c.868G>A	p.Gly290Arg	missense_variant	8/8	3		ENSP00000387092.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000422 AC: 106 AN: 251132 Hom.: 0 AF XY: 0.000420 AC XY: 57 AN XY: 135798

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461080 Hom.: 1 Cov.: 31 AF XY: 0.000292 AC XY: 212 AN XY: 726800

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74472

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor X deficiency disease Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Precision Medicine, Vanderbilt University Medical Center

Mar 16, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2021

Reported as associated with risk for Factor X deficiency (Bastarache et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29590070) -

Factor X deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.41	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.50	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.23
Sift	Benign	0.094	T;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.99	D;D
Vest4		0.49
MutPred		0.39		Loss of loop (P = 0.0804);.;
MVP		0.69
ClinPred		0.025	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149212700; hg19: chr13-113803236; COSMIC: COSV65020894; COSMIC: COSV65020894;