4-88099374-A-T

Position:

• chr4-88099374-A-T

Variant summary

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

The NM_004827.3(ABCG2):​c.1442T>A​(p.Met481Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ABCG2 NM_004827.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG2	NM_004827.3	c.1442T>A	p.Met481Lys	missense_variant	12/16	ENST00000237612.8	NP_004818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG2	ENST00000237612.8	c.1442T>A	p.Met481Lys	missense_variant	12/16	1	NM_004827.3	ENSP00000237612.3
ABCG2	ENST00000515655.5	c.1442T>A	p.Met481Lys	missense_variant	12/16	1		ENSP00000426917.1
ABCG2	ENST00000650821.1	c.1442T>A	p.Met481Lys	missense_variant	13/17			ENSP00000498246.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Sep 04, 2024

The c.1442T>A (p.M481K) alteration is located in exon 12 (coding exon 11) of the ABCG2 gene. This alteration results from a T to A substitution at nucleotide position 1442, causing the methionine (M) at amino acid position 481 to be replaced by a lysine (K). 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	0.48
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Uncertain	0.46	.;T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.36	T;T
Sift4G	Benign	0.098	T;T
Polyphen		0.22	B;B
Vest4		0.78
MutPred		0.68		Gain of catalytic residue at M481 (P = 0.0327);Gain of catalytic residue at M481 (P = 0.0327);
MVP		0.57
MPC		0.054
ClinPred		0.59	D
GERP RS		2.6
Varity_R		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-89020526;