4-88113437-C-T

Position:

• chr4-88113437-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

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 (no stars). 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 no assertion criteria provided 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 -5 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 no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG2	NM_004827.3	c.1060G>A	p.Gly354Arg	missense_variant	9/16	ENST00000237612.8	NP_004818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG2	ENST00000237612.8	c.1060G>A	p.Gly354Arg	missense_variant	9/16	1	NM_004827.3	ENSP00000237612.3
ABCG2	ENST00000515655.5	c.1060G>A	p.Gly354Arg	missense_variant	9/16	1		ENSP00000426917.1
ABCG2	ENST00000650821.1	c.1060G>A	p.Gly354Arg	missense_variant	10/17			ENSP00000498246.1

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: 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

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
DEOGEN2	Benign	0.049	.;T
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
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;