4-88101287-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004827.3(ABCG2):ā€‹c.1310A>Gā€‹(p.Gln437Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

ABCG2
NM_004827.3 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCG2NM_004827.3 linkc.1310A>G p.Gln437Arg missense_variant Exon 11 of 16 ENST00000237612.8 NP_004818.2 Q9UNQ0-1A1LUE4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCG2ENST00000237612.8 linkc.1310A>G p.Gln437Arg missense_variant Exon 11 of 16 1 NM_004827.3 ENSP00000237612.3 Q9UNQ0-1
ABCG2ENST00000515655.5 linkc.1310A>G p.Gln437Arg missense_variant Exon 11 of 16 1 ENSP00000426917.1 Q9UNQ0-2
ABCG2ENST00000650821.1 linkc.1310A>G p.Gln437Arg missense_variant Exon 12 of 17 ENSP00000498246.1 Q9UNQ0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251386
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
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:
1461880
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 17, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1310A>G (p.Q437R) alteration is located in exon 11 (coding exon 10) of the ABCG2 gene. This alteration results from a A to G substitution at nucleotide position 1310, causing the glutamine (Q) at amino acid position 437 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.053
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Pathogenic
3.2
M;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-2.7
D;D
REVEL
Pathogenic
0.82
Sift
Benign
0.046
D;T
Sift4G
Benign
0.35
T;T
Polyphen
0.96
D;D
Vest4
0.88
MutPred
0.82
Gain of methylation at Q437 (P = 0.0186);Gain of methylation at Q437 (P = 0.0186);
MVP
0.85
MPC
0.20
ClinPred
0.78
D
GERP RS
5.8
Varity_R
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747309767; hg19: chr4-89022439; API