7-65873273-G-T

Variant names:

• chr7-65873273-G-T
• rs867523491
• NM_173517.6:c.-99G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173517.6(VKORC1L1):​c.-99G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 844,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: VKORC1L1 NM_173517.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.554
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

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.-99G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_775788.2
	VKORC1L1	NM_173517.6	MANE Select	c.-99G>T		5_prime_UTR	Exon 1 of 3	NP_775788.2
	VKORC1L1	NM_001284342.3		c.-99G>T		5_prime_UTR_premature_start_codon_gain	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.-99G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000353998.2	Q8N0U8-1
	VKORC1L1	ENST00000360768.5	TSL:1 MANE Select	c.-99G>T		5_prime_UTR	Exon 1 of 3	ENSP00000353998.2	Q8N0U8-1
	VKORC1L1	ENST00000880558.1		c.-99G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000550617.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000118 AC: 10 AN: 844114 Hom.: 0 Cov.: 23 AF XY: 0.00000510 AC XY: 2 AN XY: 391964

African (AFR) AF: 0.00 AC: 0 AN: 15980

American (AMR) AF: 0.00 AC: 0 AN: 1488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5578

East Asian (EAS) AF: 0.00 AC: 0 AN: 4636

South Asian (SAS) AF: 0.00 AC: 0 AN: 17294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1694

European-Non Finnish (NFE) AF: 0.0000117 AC: 9 AN: 767282

Other (OTH) AF: 0.0000357 AC: 1 AN: 28036

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.67
FATHMM_MKL	Benign	0.0019	N
PhyloP100		-0.55
GERP RS		2.0
PromoterAI		-0.027	Neutral
Mutation Taster		=300/0	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: rs867523491; hg19: chr7-65338260;