chr13-113122883-C-T

Variant names:

• chr13-113122883-C-T
• rs2142244681
• NM_000504.4:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000504.4(F10):​c.28C>T​(p.Leu10Phe) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: F10 NM_000504.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36395842).

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.28C>T	p.Leu10Phe	missense	Exon 1 of 8	NP_000495.1	Q5JVE7
	F10	NM_001312674.2		c.28C>T	p.Leu10Phe	missense	Exon 1 of 7	NP_001299603.1
	F10	NM_001312675.2		c.28C>T	p.Leu10Phe	missense	Exon 1 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.28C>T	p.Leu10Phe	missense	Exon 1 of 8	ENSP00000364709.3	P00742
	F10	ENST00000375551.7	TSL:1	c.28C>T	p.Leu10Phe	missense	Exon 1 of 8	ENSP00000364701.3	Q5JVE8
	F10	ENST00000410083.6	TSL:1	n.28C>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000386320.2	F8WBM7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Factor X deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.36	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.088	T
Polyphen		0.78	P
Vest4		0.25
MutPred		0.36		Gain of sheet (P = 0.039)
MVP		0.98
MPC		0.56
ClinPred		0.68	D
GERP RS		3.0
PromoterAI		-0.037	Neutral
Varity_R		0.17
gMVP		0.72
Mutation Taster		=77/23	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: rs2142244681; hg19: chr13-113777197;