rs104894540

Positions:

• chr16-31094596-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5

The NM_024006.6(VKORC1):​c.134T>C​(p.Val45Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.68

Genes affected

VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_024006.6 (VKORC1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_024006.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 16-31094596-A-G is Pathogenic according to our data. Variant chr16-31094596-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31094596-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.134T>C	p.Val45Ala	missense_variant	1/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.134T>C	p.Val45Ala	missense_variant	1/4		NP_001298240.1
VKORC1	NM_206824.3	c.134T>C	p.Val45Ala	missense_variant	1/2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.134T>C	p.Val45Ala	missense_variant	1/3	1	NM_024006.6	ENSP00000378426	P1
	ENST00000624508.1	n.870A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457396 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724968

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Warfarin response Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 05, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;.;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;.;.;M;M;M
MutationTaster	Benign	0.68	A;A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	.;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0090	.;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.97, 0.99	.;.;.;D;.;D
Vest4		0.64, 0.79, 0.68, 0.53
MutPred		0.85		Loss of stability (P = 0.0972);Loss of stability (P = 0.0972);Loss of stability (P = 0.0972);Loss of stability (P = 0.0972);Loss of stability (P = 0.0972);Loss of stability (P = 0.0972);
MVP		0.78
MPC		0.55
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.78

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: rs104894540; hg19: chr16-31105917;