chr4-88097518-C-T

Variant names:

• chr4-88097518-C-T
• rs45605536
• NM_004827.3:c.1582G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004827.3(ABCG2):​c.1582G>A​(p.Ala528Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00163 in 1,614,190 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.74
• Publications: 25 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0121077895).
• BP6: Variant 4-88097518-C-T is Benign according to our data. Variant chr4-88097518-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3041649.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.1582G>A	p.Ala528Thr	missense	Exon 13 of 16	NP_004818.2	Q9UNQ0-1
	ABCG2	NM_001348985.1		c.1582G>A	p.Ala528Thr	missense	Exon 14 of 17	NP_001335914.1	Q9UNQ0-1
	ABCG2	NM_001348986.2		c.1582G>A	p.Ala528Thr	missense	Exon 13 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.1582G>A	p.Ala528Thr	missense	Exon 13 of 16	ENSP00000237612.3	Q9UNQ0-1
	ABCG2	ENST00000515655.5	TSL:1	c.1582G>A	p.Ala528Thr	missense	Exon 13 of 16	ENSP00000426917.1	Q9UNQ0-2
	ABCG2	ENST00000889086.1		c.1669G>A	p.Ala557Thr	missense	Exon 14 of 17	ENSP00000559145.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00152 AC: 383 AN: 251258 AF XY: 0.00155

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00167 AC: 2434 AN: 1461842 Hom.: 4 Cov.: 32 AF XY: 0.00164 AC XY: 1189 AN XY: 727212

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00987 AC: 258 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00175 AC: 1941 AN: 1111976

Other (OTH) AF: 0.00185 AC: 112 AN: 60394

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74498

African (AFR) AF: 0.000385 AC: 16 AN: 41580

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00139

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ABCG2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.071
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.26
Sift	Benign	0.24	T
Sift4G	Benign	0.069	T
Polyphen		0.17	B
Vest4		0.71
MVP		0.67
MPC		0.036
ClinPred		0.018	T
GERP RS		5.5
Varity_R		0.45
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs45605536; hg19: chr4-89018670; COSMIC: COSV99031603;