13-113122915-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000504.4(F10):c.60C>T(p.Leu20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,609,904 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (43 hom.)
• Consequence: F10 NM_000504.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.72

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-113122915-C-T is Benign according to our data. Variant chr13-113122915-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311269.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-3.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00501 (764/152346) while in subpopulation NFE AF= 0.00826 (562/68028). AF 95% confidence interval is 0.0077. There are 1 homozygotes in gnomad4. There are 353 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
F10	NM_000504.4	c.60C>T	p.Leu20=	synonymous_variant	1/8	ENST00000375559.8
F10	NM_001312674.2	c.60C>T	p.Leu20=	synonymous_variant	1/7
F10	NM_001312675.2	c.60C>T	p.Leu20=	synonymous_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
F10	ENST00000375559.8	c.60C>T	p.Leu20=	synonymous_variant	1/8	1	NM_000504.4	P1

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00826

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00491 AC: 1210 AN: 246452 Hom.: 5 AF XY: 0.00498 AC XY: 668 AN XY: 134060

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00620

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00335

Gnomad NFE exome AF: 0.00772

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00695 AC: 10134 AN: 1457558 Hom.: 43 Cov.: 32 AF XY: 0.00680 AC XY: 4934 AN XY: 725266

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00390

Gnomad4 NFE exome AF: 0.00815

Gnomad4 OTH exome AF: 0.00598

GnomAD4 genome AF: 0.00501 AC: 764 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00474 AC XY: 353 AN XY: 74504

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00826

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00665 Hom.: 4

Bravo AF: 0.00501

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Factor X deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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	-0.80
Cadd	Benign	0.26
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs3211718; hg19: chr13-113777229;