rs5962

chr13-113140947-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000504.4(F10):c.399C>T(p.Asn133=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,112 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (72 hom.)
• Consequence: F10 NM_000504.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 13-113140947-C-T is Benign according to our data. Variant chr13-113140947-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 311274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F10	NM_000504.4	c.399C>T	p.Asn133=	synonymous_variant	5/8	ENST00000375559.8
F10	NM_001312675.2	c.399C>T	p.Asn133=	synonymous_variant	5/8
F10	NM_001312674.2	c.370+1477C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F10	ENST00000375559.8	c.399C>T	p.Asn133=	synonymous_variant	5/8	1	NM_000504.4	P1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2586 AN: 152230 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00496 AC: 1247 AN: 251294 Hom.: 33 AF XY: 0.00387 AC XY: 526 AN XY: 135892

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00326

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000766

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00233 AC: 3403 AN: 1461764 Hom.: 72 Cov.: 31 AF XY: 0.00214 AC XY: 1556 AN XY: 727186

Gnomad4 AFR exome AF: 0.0557

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.00176

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000759

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.0170 AC: 2589 AN: 152348 Hom.: 63 Cov.: 32 AF XY: 0.0164 AC XY: 1221 AN XY: 74490

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00539 Hom.: 20

Bravo AF: 0.0189

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary factor X deficiency disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.85
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs5962; hg19: chr13-113795261;