4-88113437-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004827.3(ABCG2):c.1060G>A(p.Gly354Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,994 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (8 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

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 -2 ACMG points.

• BP6: Variant 4-88113437-C-T is Benign according to our data. Variant chr4-88113437-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044880.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.1060G>A	p.Gly354Arg	missense_variant	9/16	ENST00000237612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG2	ENST00000237612.8	c.1060G>A	p.Gly354Arg	missense_variant	9/16	1	NM_004827.3	P1
ABCG2	ENST00000515655.5	c.1060G>A	p.Gly354Arg	missense_variant	9/16	1
ABCG2	ENST00000650821.1	c.1060G>A	p.Gly354Arg	missense_variant	10/17			P1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152000 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00257 AC: 646 AN: 251282 Hom.: 1 AF XY: 0.00249 AC XY: 338 AN XY: 135792

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00357 AC: 5219 AN: 1461876 Hom.: 8 Cov.: 31 AF XY: 0.00350 AC XY: 2543 AN XY: 727240

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.00421

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00277 AC: 421 AN: 152118 Hom.: 1 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74352

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00269

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00264 AC: 320

EpiCase AF: 0.00387

EpiControl AF: 0.00373

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

Feb 23, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
Dann	Benign	0.63
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.16	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.088
Sift	Benign	0.30	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.052	B;B
Vest4		0.12
MutPred		0.35		Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);
MVP		0.32
MPC		0.033
ClinPred		0.0021	T
GERP RS		-6.2
Varity_R		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs138606116; hg19: chr4-89034589;