rs2231137

Positions:

• chr4-88139962-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004827.3(ABCG2):​c.34G>A​(p.Val12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,613,912 control chromosomes in the GnomAD database, including 6,281 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,Affects,association (no stars).

• Frequency:
  • Genomes: 𝑓 0.078 (846 hom., cov: 33)
  • Exomes 𝑓: 0.060 (5435 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Likely benign; Affects; association no assertion criteria provided B:1 O:2
• Conservation: PhyloP100: 0.210

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050233305).
• BP6: Variant 4-88139962-C-T is Benign according to our data. Variant chr4-88139962-C-T is described in ClinVar as [Likely_benign, Affects, association]. Clinvar id is 30386.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG2	NM_004827.3	c.34G>A	p.Val12Met	missense_variant	2/16	ENST00000237612.8	NP_004818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG2	ENST00000237612.8	c.34G>A	p.Val12Met	missense_variant	2/16	1	NM_004827.3	ENSP00000237612	P1

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11894 AN: 152128 Hom.: 837 Cov.: 33

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0979

GnomAD3 exomes AF: 0.114 AC: 28639 AN: 250804 Hom.: 2765 AF XY: 0.109 AC XY: 14835 AN XY: 135550

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0598 AC: 87391 AN: 1461666 Hom.: 5435 Cov.: 31 AF XY: 0.0618 AC XY: 44971 AN XY: 727126

Gnomad4 AFR exome AF: 0.0638

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0792

GnomAD4 genome AF: 0.0783 AC: 11926 AN: 152246 Hom.: 846 Cov.: 33 AF XY: 0.0867 AC XY: 6452 AN XY: 74436

Gnomad4 AFR AF: 0.0638

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.0371

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0602 Hom.: 1037

Bravo AF: 0.0829

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.0378 AC: 325

ExAC AF: 0.106 AC: 12868

Asia WGS AF: 0.254 AC: 882 AN: 3478

EpiCase AF: 0.0453

EpiControl AF: 0.0469

ClinVar

Significance: Likely benign; Affects; association

Submissions summary: Benign:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

ABCG2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 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). -

Uric acid concentration, serum, quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

Blood group, Junior system Other:1

Affects, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.6
DANN	Benign	0.054
DEOGEN2	Benign	0.041	.;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00089	N
LIST_S2	Benign	0.21	T;T;.;T
MetaRNN	Benign	0.0050	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.69	N;N;N;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;D;.
Sift4G	Benign	1.0	T;T;.;.
Polyphen		0.0070	B;B;.;.
Vest4		0.075
MPC		0.030
ClinPred		0.00058	T
GERP RS		1.5
Varity_R		0.021

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: rs2231137; hg19: chr4-89061114; COSMIC: COSV52945187;