4-88099363-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004827.3(ABCG2):c.1453C>A(p.Pro485Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG2	NM_004827.3	c.1453C>A	p.Pro485Thr	missense_variant	12/16	ENST00000237612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG2	ENST00000237612.8	c.1453C>A	p.Pro485Thr	missense_variant	12/16	1	NM_004827.3	P1
ABCG2	ENST00000515655.5	c.1453C>A	p.Pro485Thr	missense_variant	12/16	1
ABCG2	ENST00000650821.1	c.1453C>A	p.Pro485Thr	missense_variant	13/17			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000547

EpiControl AF: 0.00

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 26, 2023

The c.1453C>A (p.P485T) alteration is located in exon 12 (coding exon 11) of the ABCG2 gene. This alteration results from a C to A substitution at nucleotide position 1453, causing the proline (P) at amino acid position 485 to be replaced by a threonine (T). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.80	P;P
Vest4		0.45
MutPred		0.76		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.76
MPC		0.096
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
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: chr4-89020515;