4-88097518-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004827.3(ABCG2):c.1582G>A(p.Ala528Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,614,190 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.74

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0121077895).
• BP6: Variant 4-88097518-C-T is Benign according to our data. Variant chr4-88097518-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041649.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG2	NM_004827.3	c.1582G>A	p.Ala528Thr	missense_variant	13/16	ENST00000237612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG2	ENST00000237612.8	c.1582G>A	p.Ala528Thr	missense_variant	13/16	1	NM_004827.3	P1
ABCG2	ENST00000515655.5	c.1582G>A	p.Ala528Thr	missense_variant	13/16	1
ABCG2	ENST00000650821.1	c.1582G>A	p.Ala528Thr	missense_variant	14/17			P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00152 AC: 383 AN: 251258 Hom.: 1 AF XY: 0.00155 AC XY: 210 AN XY: 135776

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00167 AC: 2434 AN: 1461842 Hom.: 4 Cov.: 32 AF XY: 0.00164 AC XY: 1189 AN XY: 727212

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00987

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74498

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00139

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ABCG2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.071
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.26
Sift	Benign	0.24	T;T
Sift4G	Benign	0.069	T;D
Polyphen		0.17	B;B
Vest4		0.71
MVP		0.67
MPC		0.036
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs45605536; hg19: chr4-89018670; COSMIC: COSV99031603;