4-88131171-G-T

Position:

chr4-88131171-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004827.3(ABCG2):c.421C>A(p.Gln141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,854 control chromosomes in the GnomAD database, including 12,079 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.093 ( 973 hom., cov: 32)

Exomes 𝑓: 0.11 ( 11106 hom. )

Consequence

ABCG2
NM_004827.3 missense

Scores

Clinical Significance

drug response reviewed by expert panel B:1O:5

Conservation

PhyloP100: 1.82

Variant links:

Genes affected

ABCG2 (HGNC:74): (ATP binding cassette subfamily G member 2 (JR blood group)) The membrane-associated protein encoded by this gene is included in the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. Alternatively referred to as a breast cancer resistance protein, this protein functions as a xenobiotic transporter which may play a major role in multi-drug resistance. It likely serves as a cellular defense mechanism in response to mitoxantrone and anthracycline exposure. Significant expression of this protein has been observed in the placenta, which may suggest a potential role for this molecule in placenta tissue. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ABCG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002105534).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG2	NM_004827.3 linkuse as main transcript	c.421C>A	p.Gln141Lys	missense_variant	5/16	ENST00000237612.8	NP_004818.2	Q9UNQ0-1A1LUE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCG2	ENST00000237612.8 linkuse as main transcript	c.421C>A	p.Gln141Lys	missense_variant	5/16	1	NM_004827.3	ENSP00000237612.3	Q9UNQ0-1
ABCG2	ENST00000515655.5 linkuse as main transcript	c.421C>A	p.Gln141Lys	missense_variant	5/16	1		ENSP00000426917.1	Q9UNQ0-2
ABCG2	ENST00000650821.1 linkuse as main transcript	c.421C>A	p.Gln141Lys	missense_variant	6/17			ENSP00000498246.1	Q9UNQ0-1

Frequencies

GnomAD3 genomes

AF:

0.0929

AC:

14129

AN:

152046

Hom.:

968

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0299

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0669

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.0952

Gnomad FIN

AF:

0.0703

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0880

GnomAD3 exomes

AF:

0.125

AC:

31308

AN:

251158

Hom.:

2764

AF XY:

0.118

AC XY:

16075

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.0265

Gnomad AMR exome

AF:

0.225

Gnomad ASJ exome

AF:

0.0653

Gnomad EAS exome

AF:

0.305

Gnomad SAS exome

AF:

0.0932

Gnomad FIN exome

AF:

0.0724

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.114

AC:

166367

AN:

1461690

Hom.:

11106

Cov.:

AF XY:

0.112

AC XY:

81701

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.215

Gnomad4 ASJ exome

AF:

0.0652

Gnomad4 EAS exome

AF:

0.297

Gnomad4 SAS exome

AF:

0.0899

Gnomad4 FIN exome

AF:

0.0734

Gnomad4 NFE exome

AF:

0.111

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.0930

AC:

14145

AN:

152164

Hom.:

973

Cov.:

AF XY:

0.0930

AC XY:

6922

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0298

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.0669

Gnomad4 EAS

AF:

0.310

Gnomad4 SAS

AF:

0.0946

Gnomad4 FIN

AF:

0.0703

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.0890

Alfa

AF:

0.101

Hom.:

1568

Bravo

AF:

0.0987

TwinsUK

AF:

0.112

AC:

414

ALSPAC

AF:

0.104

AC:

400

ESP6500AA

AF:

0.0322

AC:

142

ESP6500EA

AF:

0.111

AC:

957

ExAC

AF:

0.118

AC:

14325

Asia WGS

AF:

0.174

AC:

603

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Benign:1Other:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

ABCG2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Uric acid concentration, serum, quantitative trait locus 1

Other:1

association, no assertion criteria provided

literature only

OMIM

Nov 04, 2009

- -

Blood group, Junior system

Other:1

association, no assertion criteria provided

literature only

OMIM

Mar 18, 2013

- -

rosuvastatin response - Metabolism/PK

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: Metabolism/PK

Gemcitabine response

Other:1

drug response, criteria provided, single submitter

research

Bioinformatics Institute, Agency for Science, Technology and Research

Jan 01, 2017

- correlated with patient outcome with gemcitabine-based chemotherpy

rosuvastatin response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

.;T

Eigen

Benign

-0.025

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.33

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.11

Sift

Benign

0.14

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.44

B;B

Vest4

0.17

MPC

0.037

ClinPred

0.033

GERP RS

5.4

Varity_R

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over