rs121964948

Variant names:

• chr13-113147490-A-T
• rs121964948
• NM_000504.4:c.859A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000504.4(F10):​c.859A>T​(p.Arg287Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: F10 NM_000504.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.88
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity FA10_HUMAN there are 21 pathogenic changes around while only 2 benign (91%) in NM_000504.4
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 13-113147490-A-T is Pathogenic according to our data. Variant chr13-113147490-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12059.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F10	NM_000504.4	c.859A>T	p.Arg287Trp	missense_variant	Exon 7 of 8	ENST00000375559.8	NP_000495.1
F10	NM_001312674.2	c.727A>T	p.Arg243Trp	missense_variant	Exon 6 of 7		NP_001299603.1
F10	NM_001312675.2	c.855+4A>T		splice_region_variant, intron_variant	Intron 7 of 7		NP_001299604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F10	ENST00000375559.8	c.859A>T	p.Arg287Trp	missense_variant	Exon 7 of 8	1	NM_000504.4	ENSP00000364709.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Factor X deficiency Pathogenic:1

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.38	T;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.1	.;M
PhyloP100		1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.55
MutPred		0.72		Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);
MVP		0.95
MPC		1.5
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.61
gMVP		0.96
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs121964948; hg19: chr13-113801804;