rs34783571

Positions:

• chr4-88092344-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004827.3(ABCG2):​c.1858G>A​(p.Asp620Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00507 in 1,612,956 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (58 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064156353).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00332 (506/152276) while in subpopulation SAS AF= 0.0191 (92/4816). AF 95% confidence interval is 0.0159. There are 2 homozygotes in gnomad4. There are 273 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG2	NM_004827.3	c.1858G>A	p.Asp620Asn	missense_variant	16/16	ENST00000237612.8	NP_004818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG2	ENST00000237612.8	c.1858G>A	p.Asp620Asn	missense_variant	16/16	1	NM_004827.3	ENSP00000237612.3
ABCG2	ENST00000515655	c.*12G>A		3_prime_UTR_variant	16/16	1		ENSP00000426917.1
ABCG2	ENST00000650821.1	c.1858G>A	p.Asp620Asn	missense_variant	17/17			ENSP00000498246.1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152158 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00520 AC: 1291 AN: 248078 Hom.: 17 AF XY: 0.00618 AC XY: 829 AN XY: 134236

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00525 AC: 7669 AN: 1460680 Hom.: 58 Cov.: 30 AF XY: 0.00577 AC XY: 4191 AN XY: 726528

Gnomad4 AFR exome AF: 0.000778

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00481

Gnomad4 OTH exome AF: 0.00451

GnomAD4 genome AF: 0.00332 AC: 506 AN: 152276 Hom.: 2 Cov.: 32 AF XY: 0.00367 AC XY: 273 AN XY: 74456

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00422 Hom.: 2

Bravo AF: 0.00317

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00554 AC: 673

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00497

EpiControl AF: 0.00599

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.085
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.25
Sift	Benign	0.069	T
Sift4G	Uncertain	0.036	D
Polyphen		0.088	B
Vest4		0.31
MVP		0.72
MPC		0.032
ClinPred		0.024	T
GERP RS		4.4
Varity_R		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34783571; hg19: chr4-89013496; COSMIC: COSV52946855;