7-65954262-G-T

Variant names:

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

Variant summary

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

The NM_173517.6(VKORC1L1):​c.493G>T​(p.Glu165*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VKORC1L1 NM_173517.6 stop_gained
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1L1	NM_173517.6	c.493G>T	p.Glu165*	stop_gained	Exon 3 of 3	ENST00000360768.5	NP_775788.2
VKORC1L1	XM_011515831.3	c.406G>T	p.Glu136*	stop_gained	Exon 4 of 4		XP_011514133.1
VKORC1L1	NM_001284342.3	c.383G>T	p.Arg128Leu	missense_variant	Exon 2 of 2		NP_001271271.1
VKORC1L1	XM_047419923.1	c.782G>T	p.Arg261Leu	missense_variant	Exon 4 of 4		XP_047275879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1L1	ENST00000360768.5	c.493G>T	p.Glu165*	stop_gained	Exon 3 of 3	1	NM_173517.6	ENSP00000353998.2
VKORC1L1	ENST00000648187.1	c.634G>T	p.Glu212*	stop_gained	Exon 3 of 3			ENSP00000497458.1
VKORC1L1	ENST00000648179.1	c.493G>T	p.Glu165*	stop_gained	Exon 3 of 3			ENSP00000497394.1
VKORC1L1	ENST00000434382.2	c.383G>T	p.Arg128Leu	missense_variant	Exon 2 of 2	2		ENSP00000403077.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

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	0.27
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.5
Vest4		0.26
ClinPred		0.85	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=19/181	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: COSV62488330;