4-88097565-G-T

Variant names:

• chr4-88097565-G-T
• rs1002012563
• NM_004827.3:c.1535C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004827.3(ABCG2):​c.1535C>A​(p.Thr512Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG2	NM_004827.3	c.1535C>A	p.Thr512Asn	missense_variant	Exon 13 of 16	ENST00000237612.8	NP_004818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG2	ENST00000237612.8	c.1535C>A	p.Thr512Asn	missense_variant	Exon 13 of 16	1	NM_004827.3	ENSP00000237612.3
ABCG2	ENST00000515655.5	c.1535C>A	p.Thr512Asn	missense_variant	Exon 13 of 16	1		ENSP00000426917.1
ABCG2	ENST00000650821.1	c.1535C>A	p.Thr512Asn	missense_variant	Exon 14 of 17			ENSP00000498246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251070 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.095	T;D
Polyphen		0.99	D;P
Vest4		0.67
MutPred		0.64		Gain of catalytic residue at F511 (P = 0.6256);Gain of catalytic residue at F511 (P = 0.6256);
MVP		0.68
MPC		0.071
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1002012563; hg19: chr4-89018717;