Genetic Variant ABCG2:p.Ile399Phe (chr4-88107266-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004827.3(ABCG2):c.1195A>T(p.Ile399Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ABCG2
NM_004827.3 missense, splice_region

Scores

Splicing: ADA: 0.0006249

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.04

Publications

0 publications found

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]

ABCG2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08448124).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCG2	NM_004827.3	MANE Select	c.1195A>T	p.Ile399Phe	missense splice_region	Exon 10 of 16	NP_004818.2	Q9UNQ0-1
ABCG2	NM_001348985.1		c.1195A>T	p.Ile399Phe	missense splice_region	Exon 11 of 17	NP_001335914.1	Q9UNQ0-1
ABCG2	NM_001348986.2		c.1195A>T	p.Ile399Phe	missense splice_region	Exon 10 of 16	NP_001335915.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCG2	ENST00000237612.8	TSL:1 MANE Select	c.1195A>T	p.Ile399Phe	missense splice_region	Exon 10 of 16	ENSP00000237612.3	Q9UNQ0-1
ABCG2	ENST00000515655.5	TSL:1	c.1195A>T	p.Ile399Phe	missense splice_region	Exon 10 of 16	ENSP00000426917.1	Q9UNQ0-2
ABCG2	ENST00000889086.1		c.1282A>T	p.Ile428Phe	missense splice_region	Exon 11 of 17	ENSP00000559145.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.29

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.015

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

-4.0

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.21

Sift

Benign

0.16

Sift4G

Benign

0.62

Polyphen

0.14

Vest4

0.16

MutPred

0.56

Loss of helix (P = 0.0167)

MVP

0.19

MPC

0.043

ClinPred

0.26

GERP RS

-12

Varity_R

0.29

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over