rs61753266

Variant names:

• chr13-113140972-G-A
• rs61753266
• NM_000504.4:c.424G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The ENST00000375559.8(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. 13/21 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 ENST00000375559.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:4
• Conservation: PhyloP100: 0.474
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• congenital factor X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1975 (below the threshold of 3.09). Trascript score misZ: 2.0489 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital factor X deficiency.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375559.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	NM_000504.4	MANE Select	c.424G>A	p.Glu142Lys	missense	Exon 5 of 8	NP_000495.1
	F10	NM_001312675.2		c.424G>A	p.Glu142Lys	missense	Exon 5 of 8	NP_001299604.1
	F10	NM_001312674.2		c.370+1502G>A		intron	N/A	NP_001299603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	ENST00000375559.8	TSL:1 MANE Select	c.424G>A	p.Glu142Lys	missense	Exon 5 of 8	ENSP00000364709.3
	F10	ENST00000375551.7	TSL:1	c.424G>A	p.Glu142Lys	missense	Exon 5 of 8	ENSP00000364701.3
	F10	ENST00000410083.6	TSL:1	n.*383G>A		non_coding_transcript_exon	Exon 5 of 7	ENSP00000386320.2

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

GnomAD2 exomes AF: 0.00445 AC: 1118 AN: 251310 AF XY: 0.00468

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 137 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00339 AC: 292 AN: 86258

European-Finnish (FIN) AF: 0.0186 AC: 990 AN: 53320

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00347 AC: 3862 AN: 1112006

Other (OTH) AF: 0.00343 AC: 207 AN: 60396

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74492

African (AFR) AF: 0.000818 AC: 34 AN: 41584

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00305 Hom.: 4

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	1	not provided (4)
1	1	-	Factor X deficiency (2)
-	2	-	Hereditary factor X deficiency disease (2)
-	-	2	not specified (2)
-	1	-	Abnormal bleeding (1)
-	-	1	F10-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.059	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.47
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.61
Sift	Benign	0.76	T
Sift4G	Benign	0.77	T
Polyphen		0.99	D
Vest4		0.46
MVP		0.98
MPC		1.3
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.54
gMVP		0.85
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

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