7-65954187-A-G

Variant names:

• chr7-65954187-A-G
• rs1000034273
• NM_173517.6:c.418A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173517.6(VKORC1L1):​c.418A>G​(p.Ile140Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VKORC1L1 NM_173517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09678927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1L1	NM_173517.6	c.418A>G	p.Ile140Val	missense_variant	Exon 3 of 3	ENST00000360768.5	NP_775788.2
VKORC1L1	NM_001284342.3	c.308A>G	p.His103Arg	missense_variant	Exon 2 of 2		NP_001271271.1
VKORC1L1	XM_047419923.1	c.707A>G	p.His236Arg	missense_variant	Exon 4 of 4		XP_047275879.1
VKORC1L1	XM_011515831.3	c.331A>G	p.Ile111Val	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.418A>G	p.Ile140Val	missense_variant	Exon 3 of 3	1	NM_173517.6	ENSP00000353998.2
VKORC1L1	ENST00000648187.1	c.559A>G	p.Ile187Val	missense_variant	Exon 3 of 3			ENSP00000497458.1
VKORC1L1	ENST00000434382.2	c.308A>G	p.His103Arg	missense_variant	Exon 2 of 2	2		ENSP00000403077.2
VKORC1L1	ENST00000648179.1	c.418A>G	p.Ile140Val	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

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418A>G (p.I140V) alteration is located in exon 3 (coding exon 3) of the VKORC1L1 gene. This alteration results from a A to G substitution at nucleotide position 418, causing the isoleucine (I) at amino acid position 140 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.95
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.097	T
MetaSVM	Uncertain	-0.095	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D
Sift4G	Benign	0.93	T
Vest4		0.24
MutPred		0.36		Gain of MoRF binding (P = 0.0141);
MVP		0.15
ClinPred		0.17	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1000034273; hg19: chr7-65419174;