16-31096368-C-T

Variant names:

• chr16-31096368-C-T
• rs9923231

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The variant allele was found at a frequency of 0.319 in 152,092 control chromosomes in the GnomAD database, including 10,015 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 (10015 hom., cov: 32)
• Consequence: Unknown
• Clinical Significance: drug response reviewed by expert panel P:1 U:2 B:4 O:8
• Conservation: PhyloP100: -0.417

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-31096368-C-T is Benign according to our data. Variant chr16-31096368-C-T is described in ClinVar as [drug_response]. Clinvar id is 2211.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, drug_response=6, other=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48521 AN: 151974 Hom.: 10014 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.319 AC: 48520 AN: 152092 Hom.: 10015 Cov.: 32 AF XY: 0.322 AC XY: 23921 AN XY: 74344

Gnomad4 AFR AF: 0.0998

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.892

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.389

Alfa AF: 0.381 Hom.: 15716

Bravo AF: 0.323

Asia WGS AF: 0.460 AC: 1603 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

Warfarin response Pathogenic:1 Other:1

Sep 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 16, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

Mar 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Thrombus Uncertain:1

-

Department of Pharmacology - Sarajevo Medical School, University Sarajevo School of Science and Technology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control;research

- -

See cases Uncertain:1

-

Department of Pharmacology - Sarajevo Medical School, University Sarajevo School of Science and Technology

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

It is uncertain if there exists an association between the presence of the variant or A allele, at the VKORC1 -1639G>A locus, and survival from thromboembolism in COVID-19 -

not specified Benign:1

Mar 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

VKORC1-related disorder Benign:1

Jul 20, 2021

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). -

Venous thromboembolism Benign:1

-

Faculty of Pharmacy, Damascus University

Significance: protective

Review Status: no assertion criteria provided

Collection Method: research

Some studies observed an association between VKORC1 -1639G>A (rs9923231) with thromboembolism (Dubovyk 2016, Kumari 2019). Our study suggests a possible protective effect for the -1639A allele against venous thromboembolism. References Dubovyk YI, Harbuzova VY, Ataman A V. G-1639A but Not C1173T VKORC1 Gene Polymorphism is Related to Ischemic Stroke and Its Various Risk Factors in Ukrainian Population. Biomed Res Int. 2016 Sep 15;2016. Kumari B, Garg I, Rai C, Panjawani U, Bhuvnesh K, Srivastava S. Positive Association of Mutations in VKORC1 and CYP2C9 Genes with Venous Thrombo-Embolism (VTE) in Indian Population: A Case Control Study. J Genet Eng Biotechnol Res. 2019;1(2). -

phenprocoumon response - Toxicity Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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: Toxicity

warfarin response - Dosage Other:1

Nov 19, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Dosage

phenprocoumon response - Dosage Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Dosage

acenocoumarol response - Dosage Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Dosage

warfarin response - Toxicity Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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: Toxicity

warfarin response - Efficacy Other:1

Mar 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: curation

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: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.5
DANN	Benign	0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9923231; hg19: chr16-31107689;