chr7-65954262-G-A

Variant names:

• chr7-65954262-G-A
• rs193921078
• NM_173517.6:c.493G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173517.6(VKORC1L1):​c.493G>A​(p.Glu165Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VKORC1L1 NM_173517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• Publications: 2 publications found

Genes affected

VKORC1L1 (HGNC:21492): (vitamin K epoxide reductase complex subunit 1 like 1) This gene encodes an enzyme important in the vitamin K cycle, which is involved in the carboxylation of glutamate residues present in vitamin K-dependent proteins. The encoded enzyme catalyzes the de-epoxidation of vitamin K 2,3-epoxide. Oxidative stress may upregulate expression of this gene and the encoded protein may protect cells and membrane proteins form oxidative damage. This gene and a related gene (Gene ID: 79001) may have arisen by gene duplication of an ancestral gene. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1L1	NM_173517.6	MANE Select	c.493G>A	p.Glu165Lys	missense	Exon 3 of 3	NP_775788.2
	VKORC1L1	NM_001284342.3		c.383G>A	p.Arg128Gln	missense	Exon 2 of 2	NP_001271271.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1L1	ENST00000360768.5	TSL:1 MANE Select	c.493G>A	p.Glu165Lys	missense	Exon 3 of 3	ENSP00000353998.2
	VKORC1L1	ENST00000648187.1		c.634G>A	p.Glu212Lys	missense	Exon 3 of 3	ENSP00000497458.1
	VKORC1L1	ENST00000434382.2	TSL:2	c.383G>A	p.Arg128Gln	missense	Exon 2 of 2	ENSP00000403077.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251396 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0049	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.64
Sift	Benign	0.23	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.40		Gain of MoRF binding (P = 5e-04)
MVP		0.50
MPC		1.3
ClinPred		0.65	D
GERP RS		5.8
Varity_R		0.21
Mutation Taster		=23/77	disease causing

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: rs193921078; hg19: chr7-65419249; COSMIC: COSV62489066;