4-88107266-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 17/22 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

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08448124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG2	NM_004827.3	c.1195A>T	p.Ile399Phe	missense_variant, splice_region_variant	10/16	ENST00000237612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG2	ENST00000237612.8	c.1195A>T	p.Ile399Phe	missense_variant, splice_region_variant	10/16	1	NM_004827.3	P1
ABCG2	ENST00000515655.5	c.1195A>T	p.Ile399Phe	missense_variant, splice_region_variant	10/16	1
ABCG2	ENST00000650821.1	c.1195A>T	p.Ile399Phe	missense_variant, splice_region_variant	11/17			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The c.1195A>T (p.I399F) alteration is located in exon 10 (coding exon 9) of the ABCG2 gene. This alteration results from a A to T substitution at nucleotide position 1195, causing the isoleucine (I) at amino acid position 399 to be replaced by a phenylalanine (F). 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	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	13
Dann	Benign	0.74
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.21
Sift	Benign	0.16	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.14	B;P
Vest4		0.16
MutPred		0.56		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.19
MPC		0.043
ClinPred		0.26	T
GERP RS		-12
Varity_R		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-89028418;