rs72552713

Variant names:

• chr4-88131805-G-A
• rs72552713
• NM_004827.3:c.376C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004827.3(ABCG2):​c.376C>T​(p.Gln126*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000377 in 1,611,534 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as association (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (9 hom.)
• Consequence: ABCG2 NM_004827.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: association no assertion criteria provided O:2
• Conservation: PhyloP100: 6.08
• Publications: 157 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High Homozygotes in GnomAdExome4 at 9 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004827.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG2	NM_004827.3	MANE Select	c.376C>T	p.Gln126*	stop_gained splice_region	Exon 4 of 16	NP_004818.2
	ABCG2	NM_001348985.1		c.376C>T	p.Gln126*	stop_gained splice_region	Exon 5 of 17	NP_001335914.1
	ABCG2	NM_001348986.2		c.376C>T	p.Gln126*	stop_gained splice_region	Exon 4 of 16	NP_001335915.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG2	ENST00000237612.8	TSL:1 MANE Select	c.376C>T	p.Gln126*	stop_gained splice_region	Exon 4 of 16	ENSP00000237612.3
	ABCG2	ENST00000515655.5	TSL:1	c.376C>T	p.Gln126*	stop_gained splice_region	Exon 4 of 16	ENSP00000426917.1
	ABCG2	ENST00000889086.1		c.376C>T	p.Gln126*	stop_gained splice_region	Exon 4 of 17	ENSP00000559145.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00655

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000396 AC: 99 AN: 250314 AF XY: 0.000355

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00518

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000392 AC: 572 AN: 1459228 Hom.: 9 Cov.: 30 AF XY: 0.000375 AC XY: 272 AN XY: 725954

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.0000224 AC: 1 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0140 AC: 557 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5046

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110660

Other (OTH) AF: 0.000216 AC: 13 AN: 60240

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00656 AC: 34 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.000212

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	BLOOD GROUP, JUNIOR SYSTEM (1)
-	-	-	URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.1
Vest4		0.97
GERP RS		5.4
Mutation Taster		=27/173	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs72552713; hg19: chr4-89052957;