chr7-65873273-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_173517.6(VKORC1L1):​c.-99G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 981,142 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 29)
  • Exomes 𝑓: 0.0075 (29 hom.)
• Consequence: VKORC1L1 NM_173517.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.554
• Publications: 1 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019835353).
• BP6: Variant 7-65873273-G-A is Benign according to our data. Variant chr7-65873273-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3777868.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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>A		5_prime_UTR	Exon 1 of 3	NP_775788.2
	VKORC1L1	NM_001284342.3		c.-99G>A		5_prime_UTR	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>A		5_prime_UTR	Exon 1 of 3	ENSP00000353998.2	Q8N0U8-1
	VKORC1L1	ENST00000648187.1		c.43G>A	p.Gly15Arg	missense	Exon 1 of 3	ENSP00000497458.1	A0A3B3ISV4
	VKORC1L1	ENST00000880558.1		c.-99G>A		5_prime_UTR	Exon 1 of 4	ENSP00000550617.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 704 AN: 136946 Hom.: 3 Cov.: 29

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.00228

Gnomad ASJ AF: 0.00379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00586

GnomAD4 exome AF: 0.00750 AC: 6331 AN: 844098 Hom.: 29 Cov.: 23 AF XY: 0.00732 AC XY: 2869 AN XY: 391954

African (AFR) AF: 0.000814 AC: 13 AN: 15980

American (AMR) AF: 0.00403 AC: 6 AN: 1488

Ashkenazi Jewish (ASJ) AF: 0.00538 AC: 30 AN: 5578

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

South Asian (SAS) AF: 0.00370 AC: 64 AN: 17294

European-Finnish (FIN) AF: 0.0212 AC: 45 AN: 2126

Middle Eastern (MID) AF: 0.00590 AC: 10 AN: 1694

European-Non Finnish (NFE) AF: 0.00782 AC: 5998 AN: 767266

Other (OTH) AF: 0.00589 AC: 165 AN: 28036

GnomAD4 genome AF: 0.00514 AC: 704 AN: 137044 Hom.: 3 Cov.: 29 AF XY: 0.00513 AC XY: 342 AN XY: 66634

African (AFR) AF: 0.00125 AC: 48 AN: 38372

American (AMR) AF: 0.00228 AC: 31 AN: 13594

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 12 AN: 3166

East Asian (EAS) AF: 0.00 AC: 0 AN: 4654

South Asian (SAS) AF: 0.00271 AC: 12 AN: 4420

European-Finnish (FIN) AF: 0.0115 AC: 90 AN: 7806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00803 AC: 498 AN: 62040

Other (OTH) AF: 0.00581 AC: 11 AN: 1892

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00408

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.88
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.020	T
PhyloP100		-0.55
GERP RS		2.0
PromoterAI		-0.038	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;