rs104894541

Positions:

• chr16-31094558-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_024006.6(VKORC1):​c.172A>G​(p.Arg58Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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)
• Consequence: VKORC1 NM_024006.6 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.90

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 2) in uniprot entity VKOR1_HUMAN there are 4 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, 0.98
• PP5: Variant 16-31094558-T-C is Pathogenic according to our data. Variant chr16-31094558-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2209.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31094558-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.172A>G	p.Arg58Gly	missense_variant, splice_region_variant	1/3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.172A>G	p.Arg58Gly	missense_variant, splice_region_variant	1/4		NP_001298240.1
VKORC1	NM_206824.3	c.172A>G	p.Arg58Gly	missense_variant, splice_region_variant	1/2		NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.172A>G	p.Arg58Gly	missense_variant, splice_region_variant	1/3	1	NM_024006.6	ENSP00000378426	P1
	ENST00000624508.1	n.832T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;.;D
Eigen	Benign	0.0072
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.22	T;D;T;D;T;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.7	.;.;.;M;M;M
MutationTaster	Benign	0.88	A;A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	.;D;D;D;N;D
REVEL	Pathogenic	0.75
Sift	Benign	0.30	.;T;D;T;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0, 0.0010	.;.;.;D;.;B
Vest4		0.41, 0.79, 0.36, 0.56
MutPred		0.92		Loss of MoRF binding (P = 0.0341);Loss of MoRF binding (P = 0.0341);Loss of MoRF binding (P = 0.0341);Loss of MoRF binding (P = 0.0341);Loss of MoRF binding (P = 0.0341);Loss of MoRF binding (P = 0.0341);
MVP		0.81
MPC		1.1
ClinPred		0.99	D
GERP RS		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894541; hg19: chr16-31105879;