16-31094596-A-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_024006.6(VKORC1):​c.134T>A​(p.Val45Glu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VKORC1 NM_024006.6 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ENSG00000255439 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a topological_domain Lumenal (size 50) in uniprot entity VKOR1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_024006.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.134T>A	p.Val45Glu	missense_variant	Exon 1 of 3	ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.134T>A	p.Val45Glu	missense_variant	Exon 1 of 4		NP_001298240.1
VKORC1	NM_206824.3	c.134T>A	p.Val45Glu	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>A	p.Val45Glu	missense_variant	Exon 1 of 3	1	NM_024006.6	ENSP00000378426.2
ENSG00000255439	ENST00000529564.1	c.134T>A	p.Val45Glu	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: 0.00000138 AC XY: 1 AN XY: 724968

Gnomad4 AFR exome AF: 0.00

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: 9.00e-7

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	0.73
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;.;.;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	.;.;.;M;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	.;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;.;D
Vest4		0.73, 0.76, 0.75, 0.75
MutPred		0.66		Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);
MVP		0.89
MPC		1.4
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.90

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: chr16-31105917;