16-31094645-C-G

Variant names:

• chr16-31094645-C-G
• NM_024006.6:c.85G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Strong

The NM_024006.6(VKORC1):​c.85G>C​(p.Val29Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,454,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76

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]

ENSG00000255439 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 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 helix (size 16) 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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.85G>C	p.Val29Leu	missense_variant	Exon 1 of 3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.85G>C	p.Val29Leu	missense_variant	Exon 1 of 4		NP_001298240.1
VKORC1	NM_206824.3	c.85G>C	p.Val29Leu	missense_variant	Exon 1 of 2		NP_996560.1
LOC124903680	XM_047435012.1	c.*239G>C		downstream_gene_variant			XP_047290968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.85G>C	p.Val29Leu	missense_variant	Exon 1 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.85G>C	p.Val29Leu	missense_variant	Exon 1 of 5	4		ENSP00000431371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454770 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723766

Gnomad4 AFR exome AF: 0.0000598

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;.;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T;T;T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;.;M;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	.;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.019	.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;T;D;T
Polyphen		1.0, 1.0	.;.;.;D;.;D
Vest4		0.67, 0.88, 0.82, 0.58
MutPred		0.95		Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);Loss of catalytic residue at V29 (P = 0.1021);
MVP		0.83
MPC		0.97
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-31105966;