13-113122816-C-T

Variant names:

• chr13-113122816-C-T
• rs3212994
• NM_000504.4:c.-40C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000504.4(F10):​c.-40C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,603,172 control chromosomes in the GnomAD database, including 1,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (94 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1057 hom.)
• Consequence: F10 NM_000504.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.54

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-113122816-C-T is Benign according to our data. Variant chr13-113122816-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 311266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0277 (4215/152360) while in subpopulation NFE AF = 0.0415 (2824/68030). AF 95% confidence interval is 0.0402. There are 94 homozygotes in GnomAd4. There are 2128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 94 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
F10	NM_000504.4	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000375559.8	NP_000495.1
F10	NM_000504.4	c.-40C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000375559.8	NP_000495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
F10	ENST00000375559	c.-40C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_000504.4	ENSP00000364709.3
F10	ENST00000375559	c.-40C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_000504.4	ENSP00000364709.3

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4217 AN: 152242 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.00629

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0273 AC: 6673 AN: 244618 AF XY: 0.0275

Gnomad AFR exome AF: 0.00711

Gnomad AMR exome AF: 0.00863

Gnomad ASJ exome AF: 0.00999

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.0236

GnomAD4 exome AF: 0.0349 AC: 50627 AN: 1450812 Hom.: 1057 Cov.: 31 AF XY: 0.0344 AC XY: 24874 AN XY: 722292

Gnomad4 AFR exome AF: 0.00521 AC: 174 AN: 33408

Gnomad4 AMR exome AF: 0.00881 AC: 394 AN: 44698

Gnomad4 ASJ exome AF: 0.0101 AC: 264 AN: 26120

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39674

Gnomad4 SAS exome AF: 0.0117 AC: 1005 AN: 86206

Gnomad4 FIN exome AF: 0.0611 AC: 2795 AN: 45748

Gnomad4 NFE exome AF: 0.0400 AC: 44325 AN: 1108972

Gnomad4 Remaining exome AF: 0.0272 AC: 1636 AN: 60226

GnomAD4 genome AF: 0.0277 AC: 4215 AN: 152360 Hom.: 94 Cov.: 33 AF XY: 0.0286 AC XY: 2128 AN XY: 74498

Gnomad4 AFR AF: 0.00627 AC: 0.00627494 AN: 0.00627494

Gnomad4 AMR AF: 0.0176 AC: 0.0175702 AN: 0.0175702

Gnomad4 ASJ AF: 0.0130 AC: 0.0129608 AN: 0.0129608

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00869 AC: 0.00868846 AN: 0.00868846

Gnomad4 FIN AF: 0.0681 AC: 0.0681304 AN: 0.0681304

Gnomad4 NFE AF: 0.0415 AC: 0.0415111 AN: 0.0415111

Gnomad4 OTH AF: 0.0161 AC: 0.0160681 AN: 0.0160681

Alfa AF: 0.0316 Hom.: 150

Bravo AF: 0.0217

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor VII deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Factor X deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.73
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3212994; hg19: chr13-113777130;