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
• Publications: 8 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: 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 Benign/Likely_benign. ClinVar VariationId 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 94 AR gene

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.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_000495.1	Q5JVE7
	F10	NM_000504.4	MANE Select	c.-40C>T		5_prime_UTR	Exon 1 of 8	NP_000495.1	Q5JVE7
	F10	NM_001312674.2		c.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001299603.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F10	ENST00000375559.8	TSL:1 MANE Select	c.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000364709.3	P00742
	F10	ENST00000375551.7	TSL:1	c.-40C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000364701.3	Q5JVE8
	F10	ENST00000375559.8	TSL:1 MANE Select	c.-40C>T		5_prime_UTR	Exon 1 of 8	ENSP00000364709.3	P00742

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

African (AFR) AF: 0.00521 AC: 174 AN: 33408

American (AMR) AF: 0.00881 AC: 394 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0117 AC: 1005 AN: 86206

European-Finnish (FIN) AF: 0.0611 AC: 2795 AN: 45748

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5760

European-Non Finnish (NFE) AF: 0.0400 AC: 44325 AN: 1108972

Other (OTH) 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

African (AFR) AF: 0.00627 AC: 261 AN: 41594

American (AMR) AF: 0.0176 AC: 269 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4834

European-Finnish (FIN) AF: 0.0681 AC: 723 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0415 AC: 2824 AN: 68030

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0316 Hom.: 150

Bravo AF: 0.0217

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Factor VII deficiency (1)
-	-	1	Factor X deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		2.5
PromoterAI		-0.060	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3212994; hg19: chr13-113777130;