rs9934438

chr16-31093557-G-Achr16-31093557-G-C

• Frequency: Genomes: 𝑓 0.32 (9985 hom., cov: 29)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: drug response reviewed by expert panel P:1 B:2 O:4
• Conservation: PhyloP100: 1.31

ACMG classification

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, Likely_benign=1, 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: GnomAd 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: 48370 AN: 151546 Hom.: 9985 Cov.: 29

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 AF XY: 0.376 AC XY: 257779 AN XY: 685662

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

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:

Submissions by phenotype

Warfarin response Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2008	- -
drug response, no assertion criteria provided	research	Pharmacogenomics Lab, Chungbuk National University	Aug 31, 2010	- likely responsive

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

- -

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

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

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

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

Cadd

Benign

14

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

Other links and lift over

dbSNP: rs9934438; hg19: chr16-31104878;