chr13-113129471-G-C

Position:

• chr13-113129471-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000375559.8(F10):​c.90G>C​(p.Gln30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,910 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q30R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (35 hom.)
• Consequence: F10 ENST00000375559.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.37

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004483044).
• BP6: Variant 13-113129471-G-C is Benign according to our data. Variant chr13-113129471-G-C is described in ClinVar as [Benign]. Clinvar id is 311270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1814/152240) while in subpopulation AFR AF= 0.0418 (1738/41532). AF 95% confidence interval is 0.0402. There are 24 homozygotes in gnomad4. There are 848 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
F10	NM_000504.4	c.90G>C	p.Gln30His	missense_variant	2/8	ENST00000375559.8	NP_000495.1
F10-AS1	NR_126424.1	n.41+535C>G		intron_variant, non_coding_transcript_variant
F10	NM_001312674.2	c.90G>C	p.Gln30His	missense_variant	2/7		NP_001299603.1
F10	NM_001312675.2	c.90G>C	p.Gln30His	missense_variant	2/8		NP_001299604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
F10	ENST00000375559.8	c.90G>C	p.Gln30His	missense_variant	2/8	1	NM_000504.4	ENSP00000364709	P1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1807 AN: 152122 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00309 AC: 776 AN: 251482 Hom.: 15 AF XY: 0.00218 AC XY: 296 AN XY: 135920

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00125 AC: 1834 AN: 1461670 Hom.: 35 Cov.: 33 AF XY: 0.00109 AC XY: 791 AN XY: 727120

Gnomad4 AFR exome AF: 0.0448

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152240 Hom.: 24 Cov.: 32 AF XY: 0.0114 AC XY: 848 AN XY: 74438

Gnomad4 AFR AF: 0.0418

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.0138

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00405 AC: 492

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Hereditary factor X deficiency disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.010
DANN	Benign	0.45
DEOGEN2	Benign	0.023	T;.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.052	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.0	.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.10
MutPred		0.12		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.68
MPC		0.48
ClinPred		0.015	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.050
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5961; hg19: chr13-113783785;