16-31096368-C-T

Position:

• chr16-31096368-C-T

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:3 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, other=1, drug_response=6}.
• 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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	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:3 Other:8

Revision: reviewed by expert panel

Submissions by phenotype

Warfarin response Pathogenic:1 Other:1

drug response, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 16, 2006	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2010	- -

Thrombus Uncertain:1

Uncertain significance, no assertion criteria provided

case-control;research

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

-

- -

See cases Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

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

-

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

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. -

VKORC1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 20, 2021

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

protective, no assertion criteria provided

research

Faculty of Pharmacy, Damascus University

-

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

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: Toxicity

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Nov 19, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

not provided Other:1

other, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 08, 2018

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

warfarin response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 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: Toxicity

warfarin response - Efficacy 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: 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;