7-65954181-T-C

Position:

• chr7-65954181-T-C

Variant summary

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

The NM_173517.6(VKORC1L1):​c.412T>C​(p.Phe138Leu) variant causes a missense 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_173517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

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/exons	MANE	Protein	UniProt
VKORC1L1	NM_173517.6	c.412T>C	p.Phe138Leu	missense_variant	3/3	ENST00000360768.5	NP_775788.2
VKORC1L1	NM_001284342.3	c.302T>C	p.Val101Ala	missense_variant	2/2		NP_001271271.1
VKORC1L1	XM_047419923.1	c.701T>C	p.Val234Ala	missense_variant	4/4		XP_047275879.1
VKORC1L1	XM_011515831.3	c.325T>C	p.Phe109Leu	missense_variant	4/4		XP_011514133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1L1	ENST00000360768.5	c.412T>C	p.Phe138Leu	missense_variant	3/3	1	NM_173517.6	ENSP00000353998	P1
VKORC1L1	ENST00000648187.1	c.553T>C	p.Phe185Leu	missense_variant	3/3			ENSP00000497458
VKORC1L1	ENST00000434382.2	c.302T>C	p.Val101Ala	missense_variant	2/2	2		ENSP00000403077
VKORC1L1	ENST00000648179.1	c.412T>C	p.Phe138Leu	missense_variant	3/3			ENSP00000497394	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.412T>C (p.F138L) alteration is located in exon 3 (coding exon 3) of the VKORC1L1 gene. This alteration results from a T to C substitution at nucleotide position 412, causing the phenylalanine (F) at amino acid position 138 to be replaced by a leucine (L). 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	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;D
Eigen	Benign	-0.053
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.5	.;L;L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	.;.;D
REVEL	Uncertain	0.42
Sift	Benign	0.13	.;.;T
Sift4G	Benign	0.40	.;.;T
Polyphen		0.032	.;B;B
Vest4		0.20
MutPred		0.51		.;Gain of ubiquitination at K136 (P = 0.1062);Gain of ubiquitination at K136 (P = 0.1062);
MVP		0.20
MPC		1.1
ClinPred		0.74	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr7-65419168;