rs9934438
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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
NM_024006.6 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.31
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 |
---|---|---|---|---|---|---|---|
VKORC1 | NM_024006.6 | c.174-136C>T | intron_variant | ENST00000394975.3 | |||
VKORC1 | NM_001311311.2 | c.174-136C>T | intron_variant | ||||
VKORC1 | NM_206824.3 | c.173+1000C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VKORC1 | ENST00000394975.3 | c.174-136C>T | intron_variant | 1 | NM_024006.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.319 AC: 48370AN: 151546Hom.: 9985 Cov.: 29
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GnomAD4 exome AF: 0.380 AC: 528705AN: 1391514Hom.: 109226 Cov.: 33 AF XY: 0.376 AC XY: 257779AN XY: 685662
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GnomAD4 genome AF: 0.319 AC: 48369AN: 151664Hom.: 9986 Cov.: 29 AF XY: 0.321 AC XY: 23820AN XY: 74112
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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 provided | research | Pharmacogenomics Lab, Chungbuk National University | Aug 31, 2010 | - likely responsive |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2008 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2018 | This 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 submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
phenprocoumon response - Dosage Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB 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 |
warfarin response - Dosage Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 29, 2021 | PharmGKB 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 |
acenocoumarol response - Dosage Other:1
drug response, reviewed by expert panel | curation | PharmGKB | Mar 24, 2021 | PharmGKB 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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at