rs104894540

Variant names:

• chr16-31094596-A-G
• rs104894540
• NM_024006.6:c.134T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-31094596-A-G
• chr16-31094596-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. 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).

• 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
• Publications: 30 publications found

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]

VKORC1 Gene-Disease associations (from GenCC):

• vitamin K-dependent clotting factors, combined deficiency of, type 2

  Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• vitamin K-dependent clotting factors, combined deficiency of, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• 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 VariationId is 2208.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.134T>C	p.Val45Ala	missense_variant	Exon 1 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.134T>C	p.Val45Ala	missense_variant	Exon 1 of 5	4		ENSP00000431371.1

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 85916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110956

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Warfarin response Pathogenic:1

Feb 05, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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
PhyloP100		4.7
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
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.78
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894540; hg19: chr16-31105917;