chr7-65873516-C-T

Variant names:

• chr7-65873516-C-T
• rs761338410
• NM_173517.6:c.145C>T

Variant summary

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

The NM_173517.6(VKORC1L1):​c.145C>T​(p.Leu49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,590,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: VKORC1L1 NM_173517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200
• Publications: 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1L1	NM_173517.6	MANE Select	c.145C>T	p.Leu49Phe	missense	Exon 1 of 3	NP_775788.2
	VKORC1L1	NM_001284342.3		c.145C>T	p.Leu49Phe	missense	Exon 1 of 2	NP_001271271.1	Q8N0U8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1L1	ENST00000360768.5	TSL:1 MANE Select	c.145C>T	p.Leu49Phe	missense	Exon 1 of 3	ENSP00000353998.2	Q8N0U8-1
	VKORC1L1	ENST00000880558.1		c.145C>T	p.Leu49Phe	missense	Exon 1 of 4	ENSP00000550617.1
	VKORC1L1	ENST00000648187.1		c.286C>T	p.Leu96Phe	missense	Exon 1 of 3	ENSP00000497458.1	A0A3B3ISV4

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000135 AC: 3 AN: 222554 AF XY: 0.0000164

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: 0.0000298

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1439456 Hom.: 0 Cov.: 33 AF XY: 0.0000154 AC XY: 11 AN XY: 716042

African (AFR) AF: 0.0000311 AC: 1 AN: 32182

American (AMR) AF: 0.00 AC: 0 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 38226

South Asian (SAS) AF: 0.00 AC: 0 AN: 84452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1103262

Other (OTH) AF: 0.0000169 AC: 1 AN: 59190

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151074 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73748

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67632

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.00061	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.5	L
PhyloP100		-0.020
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.30
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.028	B
Vest4		0.10
MutPred		0.56		Loss of helix (P = 0.1299)
MVP		0.15
MPC		1.2
ClinPred		0.053	T
GERP RS		1.3
PromoterAI		0.077	Neutral
Varity_R		0.074
gMVP		0.86
Mutation Taster		=75/25	polymorphism

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: rs761338410; hg19: chr7-65338503;