rs149212700

Variant names:

• chr13-113148922-G-A
• rs149212700
• NM_000504.4:c.872G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-113148922-G-A
• chr13-113148922-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 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. 12/18 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
• Publications: 6 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000504.4
• 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=0.012232184).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 212 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000504.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	NM_000504.4	MANE Select	c.872G>A	p.Arg291Gln	missense	Exon 8 of 8	NP_000495.1	Q5JVE7
	F10	NM_001312674.2		c.740G>A	p.Arg247Gln	missense	Exon 7 of 7	NP_001299603.1
	F10	NM_001312675.2		c.862G>A	p.Gly288Arg	missense	Exon 8 of 8	NP_001299604.1	Q5JVE8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	ENST00000375559.8	TSL:1 MANE Select	c.872G>A	p.Arg291Gln	missense	Exon 8 of 8	ENSP00000364709.3	P00742
	F10	ENST00000375551.7	TSL:1	c.862G>A	p.Gly288Arg	missense	Exon 8 of 8	ENSP00000364701.3	Q5JVE8
	F10	ENST00000858583.1		c.887G>A	p.Arg296Gln	missense	Exon 8 of 8	ENSP00000528642.1

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

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251132 AF XY: 0.000420

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52774

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000229 AC: 255 AN: 1111860

Other (OTH) AF: 0.000679 AC: 41 AN: 60384

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

African (AFR) AF: 0.000169 AC: 7 AN: 41542

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68014

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

Alfa AF: 0.000604 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Factor X deficiency (1)
-	1	-	Hereditary factor X deficiency disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.50	T
PhyloP100		1.6
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.23
Sift	Benign	0.094	T
Sift4G	Uncertain	0.046	D
Polyphen		0.99	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
Varity_R		0.51
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs149212700; hg19: chr13-113803236; COSMIC: COSV65020894; COSMIC: COSV65020894;