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rs9934438

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

The NM_024006.6(VKORC1):c.174-136C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,543,178 control chromosomes in the GnomAD database, including 119,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.32 ( 9986 hom., cov: 29)
Exomes 𝑓: 0.38 ( 109226 hom. )

Consequence

VKORC1
NM_024006.6 intron

Scores

2

Clinical Significance

drug response reviewed by expert panel P:1B:2O:4

Conservation

PhyloP100: 1.31
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 -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 16-31093557-G-A is Benign according to our data. Variant chr16-31093557-G-A is described in ClinVar as [drug_response]. Clinvar id is 37344.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=3, Benign=1, Likely_benign=1}. Variant chr16-31093557-G-A is described in Lovd as [Benign]. Variant chr16-31093557-G-A is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VKORC1NM_024006.6 linkuse as main transcriptc.174-136C>T intron_variant ENST00000394975.3
VKORC1NM_001311311.2 linkuse as main transcriptc.174-136C>T intron_variant
VKORC1NM_206824.3 linkuse as main transcriptc.173+1000C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VKORC1ENST00000394975.3 linkuse as main transcriptc.174-136C>T intron_variant 1 NM_024006.6 P1Q9BQB6-1

Frequencies

GnomAD3 genomes
AF:
0.319
AC:
48370
AN:
151546
Hom.:
9985
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.0999
Gnomad AMI
AF:
0.442
Gnomad AMR
AF:
0.391
Gnomad ASJ
AF:
0.500
Gnomad EAS
AF:
0.893
Gnomad SAS
AF:
0.179
Gnomad FIN
AF:
0.390
Gnomad MID
AF:
0.513
Gnomad NFE
AF:
0.378
Gnomad OTH
AF:
0.390
GnomAD4 exome
AF:
0.380
AC:
528705
AN:
1391514
Hom.:
109226
Cov.:
33
AF XY:
0.376
AC XY:
257779
AN XY:
685662
show subpopulations
Gnomad4 AFR exome
AF:
0.0931
Gnomad4 AMR exome
AF:
0.451
Gnomad4 ASJ exome
AF:
0.491
Gnomad4 EAS exome
AF:
0.903
Gnomad4 SAS exome
AF:
0.187
Gnomad4 FIN exome
AF:
0.391
Gnomad4 NFE exome
AF:
0.378
Gnomad4 OTH exome
AF:
0.392
GnomAD4 genome
AF:
0.319
AC:
48369
AN:
151664
Hom.:
9986
Cov.:
29
AF XY:
0.321
AC XY:
23820
AN XY:
74112
show subpopulations
Gnomad4 AFR
AF:
0.0996
Gnomad4 AMR
AF:
0.391
Gnomad4 ASJ
AF:
0.500
Gnomad4 EAS
AF:
0.893
Gnomad4 SAS
AF:
0.178
Gnomad4 FIN
AF:
0.390
Gnomad4 NFE
AF:
0.378
Gnomad4 OTH
AF:
0.389
Alfa
AF:
0.381
Hom.:
17795
Bravo
AF:
0.323
Asia WGS
AF:
0.460
AC:
1602
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Pathogenic:1Benign:2Other:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Warfarin response Pathogenic:1Other:1
drug response, no assertion criteria providedresearchPharmacogenomics Lab, Chungbuk National UniversityAug 31, 2010- likely responsive
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2008- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 09, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Vitamin K-Dependent Clotting Factors Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
warfarin response - Dosage Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 29, 2021PharmGKB Level of Evidence 1B: Level 1B clinical annotations describe variant-drug combinations with a high level of evidence supporting the association but no variant-specific prescribing guidance in an annotated clinical guideline or FDA drug label. Level 1B clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage
phenprocoumon response - Dosage Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage
acenocoumarol response - Dosage Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
Cadd
Benign
13
Dann
Benign
0.90

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

LitVar

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

Other links and lift over

dbSNP: rs9934438; hg19: chr16-31104878; API