7-65954294-G-T

Variant names:

• chr7-65954294-G-T
• NM_173517.6:c.525G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001284342.3(VKORC1L1):​c.415G>T​(p.Gly139*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VKORC1L1 NM_001284342.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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

Verdict is Uncertain_significance. Variant got 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.525G>T	p.Gln175His	missense_variant	Exon 3 of 3	ENST00000360768.5	NP_775788.2
VKORC1L1	NM_001284342.3	c.415G>T	p.Gly139*	stop_gained	Exon 2 of 2		NP_001271271.1
VKORC1L1	XM_047419923.1	c.814G>T	p.Gly272*	stop_gained	Exon 4 of 4		XP_047275879.1
VKORC1L1	XM_011515831.3	c.438G>T	p.Gln146His	missense_variant	Exon 4 of 4		XP_011514133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1L1	ENST00000360768.5	c.525G>T	p.Gln175His	missense_variant	Exon 3 of 3	1	NM_173517.6	ENSP00000353998.2
VKORC1L1	ENST00000434382.2	c.415G>T	p.Gly139*	stop_gained	Exon 2 of 2	2		ENSP00000403077.2
VKORC1L1	ENST00000648187.1	c.666G>T	p.Gln222His	missense_variant	Exon 3 of 3			ENSP00000497458.1
VKORC1L1	ENST00000648179.1	c.525G>T	p.Gln175His	missense_variant	Exon 3 of 3			ENSP00000497394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.525G>T (p.Q175H) alteration is located in exon 3 (coding exon 3) of the VKORC1L1 gene. This alteration results from a G to T substitution at nucleotide position 525, causing the glutamine (Q) at amino acid position 175 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.13
ClinPred		0.69	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: chr7-65419281;