rs1212018525

Variant names:

• chr13-113129465-G-T
• rs1212018525
• NM_000504.4:c.84G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000504.4(F10):​c.84G>T​(p.Arg28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: F10 NM_000504.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.24
• 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-AS1 (HGNC:40225): (F10 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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=0.11343372).

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.84G>T	p.Arg28Ser	missense	Exon 2 of 8	NP_000495.1	Q5JVE7
	F10	NM_001312674.2		c.84G>T	p.Arg28Ser	missense	Exon 2 of 7	NP_001299603.1
	F10	NM_001312675.2		c.84G>T	p.Arg28Ser	missense	Exon 2 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.84G>T	p.Arg28Ser	missense	Exon 2 of 8	ENSP00000364709.3	P00742
	F10	ENST00000375551.7	TSL:1	c.84G>T	p.Arg28Ser	missense	Exon 2 of 8	ENSP00000364701.3	Q5JVE8
	F10	ENST00000410083.6	TSL:1	n.84G>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000386320.2	F8WBM7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461612 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.25
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	5.1
DANN	Benign	0.89
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.5	L
PhyloP100		-1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.67	T
Sift4G	Benign	0.42	T
Polyphen		0.87	P
Vest4		0.35
MutPred		0.42		Loss of MoRF binding (P = 0.0575)
MVP		0.94
MPC		0.62
ClinPred		0.27	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.079
gMVP		0.56
Mutation Taster		=94/6	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: rs1212018525; hg19: chr13-113783779;