NM_004827.3:c.34G>A

Variant names:

• chr4-88139962-C-T
• rs2231137
• NM_004827.3:c.34G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004827.3(ABCG2):​c.34G>A​(p.Val12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,613,912 control chromosomes in the GnomAD database, including 6,281 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,Affects,association (no stars).

• Frequency:
  • Genomes: 𝑓 0.078 (846 hom., cov: 33)
  • Exomes 𝑓: 0.060 (5435 hom.)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Likely benign; Affects; association no assertion criteria provided B:1 O:2
• Conservation: PhyloP100: 0.210
• Publications: 308 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050233305).
• BP6: Variant 4-88139962-C-T is Benign according to our data. Variant chr4-88139962-C-T is described in ClinVar as Likely_benign|Affects|association. ClinVar VariationId is 30386.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

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.34G>A	p.Val12Met	missense	Exon 2 of 16	NP_004818.2	Q9UNQ0-1
	ABCG2	NM_001348985.1		c.34G>A	p.Val12Met	missense	Exon 3 of 17	NP_001335914.1	Q9UNQ0-1
	ABCG2	NM_001348986.2		c.34G>A	p.Val12Met	missense	Exon 2 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.34G>A	p.Val12Met	missense	Exon 2 of 16	ENSP00000237612.3	Q9UNQ0-1
	ABCG2	ENST00000515655.5	TSL:1	c.34G>A	p.Val12Met	missense	Exon 2 of 16	ENSP00000426917.1	Q9UNQ0-2
	ABCG2	ENST00000503830.2	TSL:1	c.34G>A	p.Val12Met	missense	Exon 2 of 4	ENSP00000426934.2	F8S0F2

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11894 AN: 152128 Hom.: 837 Cov.: 33

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.114 AC: 28639 AN: 250804 AF XY: 0.109

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0408

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0598 AC: 87391 AN: 1461666 Hom.: 5435 Cov.: 31 AF XY: 0.0618 AC XY: 44971 AN XY: 727126

African (AFR) AF: 0.0638 AC: 2135 AN: 33476

American (AMR) AF: 0.229 AC: 10228 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2744 AN: 26126

East Asian (EAS) AF: 0.265 AC: 10536 AN: 39694

South Asian (SAS) AF: 0.140 AC: 12048 AN: 86234

European-Finnish (FIN) AF: 0.124 AC: 6594 AN: 53370

Middle Eastern (MID) AF: 0.102 AC: 588 AN: 5768

European-Non Finnish (NFE) AF: 0.0339 AC: 37733 AN: 1111930

Other (OTH) AF: 0.0792 AC: 4785 AN: 60384

GnomAD4 genome AF: 0.0783 AC: 11926 AN: 152246 Hom.: 846 Cov.: 33 AF XY: 0.0867 AC XY: 6452 AN XY: 74436

African (AFR) AF: 0.0638 AC: 2650 AN: 41536

American (AMR) AF: 0.156 AC: 2382 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3472

East Asian (EAS) AF: 0.312 AC: 1616 AN: 5176

South Asian (SAS) AF: 0.157 AC: 757 AN: 4822

European-Finnish (FIN) AF: 0.128 AC: 1354 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0371 AC: 2523 AN: 68034

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.0588 Hom.: 1164

Bravo AF: 0.0829

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.0606 AC: 267

ESP6500EA AF: 0.0378 AC: 325

ExAC AF: 0.106 AC: 12868

Asia WGS AF: 0.254 AC: 882 AN: 3478

EpiCase AF: 0.0453

EpiControl AF: 0.0469

ClinVar

ClinVar submissions

Significance: Likely benign; Affects; association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ABCG2-related disorder (1)
-	-	-	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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.6
DANN	Benign	0.054
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00089	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		0.21
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.075
MPC		0.030
ClinPred		0.00058	T
GERP RS		1.5
Varity_R		0.021
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2231137; hg19: chr4-89061114; COSMIC: COSV52945187;