16-31092854-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_001311311.2(VKORC1):​c.296G>A​(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,013,254 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00091 ( 6 hom. )

Consequence

VKORC1
NM_001311311.2 missense

Scores

2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.454
Variant links:
Genes affected
VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1
In a chain Vitamin K epoxide reductase complex subunit 1 (size 162) in uniprot entity VKOR1_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_001311311.2
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 16-31092854-C-T is Benign according to our data. Variant chr16-31092854-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3045115.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VKORC1NM_024006.6 linkc.283+458G>A intron_variant Intron 2 of 2 ENST00000394975.3 NP_076869.1 Q9BQB6-1A0A0S2Z6I4
VKORC1NM_001311311.2 linkc.296G>A p.Arg99His missense_variant Exon 3 of 4 NP_001298240.1 Q9BQB6
VKORC1NM_206824.3 linkc.174-1512G>A intron_variant Intron 1 of 1 NP_996560.1 Q9BQB6-3A0A0S2Z5X7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VKORC1ENST00000394975.3 linkc.283+458G>A intron_variant Intron 2 of 2 1 NM_024006.6 ENSP00000378426.2 Q9BQB6-1
ENSG00000255439ENST00000529564.1 linkc.283+458G>A intron_variant Intron 2 of 4 4 ENSP00000431371.1 E9PLN8

Frequencies

GnomAD3 genomes
AF:
0.00108
AC:
163
AN:
151596
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000218
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000593
Gnomad ASJ
AF:
0.0274
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.000692
Gnomad OTH
AF:
0.000967
GnomAD3 exomes
AF:
0.00230
AC:
191
AN:
82994
Hom.:
2
AF XY:
0.00234
AC XY:
109
AN XY:
46632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000753
Gnomad ASJ exome
AF:
0.0301
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000687
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000782
Gnomad OTH exome
AF:
0.00330
GnomAD4 exome
AF:
0.000911
AC:
785
AN:
861540
Hom.:
6
Cov.:
12
AF XY:
0.000904
AC XY:
386
AN XY:
427030
show subpopulations
Gnomad4 AFR exome
AF:
0.00156
Gnomad4 AMR exome
AF:
0.000642
Gnomad4 ASJ exome
AF:
0.0278
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000775
Gnomad4 FIN exome
AF:
0.000173
Gnomad4 NFE exome
AF:
0.000464
Gnomad4 OTH exome
AF:
0.00218
GnomAD4 genome
AF:
0.00107
AC:
163
AN:
151714
Hom.:
1
Cov.:
31
AF XY:
0.00111
AC XY:
82
AN XY:
74116
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000593
Gnomad4 ASJ
AF:
0.0274
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000692
Gnomad4 OTH
AF:
0.000957
Alfa
AF:
0.00386
Hom.:
1
Bravo
AF:
0.00120
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

VKORC1-related disorder Benign:1
Feb 28, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
1.1
DANN
Benign
0.63

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370105350; hg19: chr16-31104175; API