4-88092254-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004827.3(ABCG2):c.1948T>C(p.Phe650Leu) variant causes a missense 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. 14/20 in silico tools predict a benign 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: 3.03

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=0.18798277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG2	NM_004827.3	c.1948T>C	p.Phe650Leu	missense_variant	16/16	ENST00000237612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG2	ENST00000237612.8	c.1948T>C	p.Phe650Leu	missense_variant	16/16	1	NM_004827.3	P1
ABCG2	ENST00000515655.5	c.*102T>C		3_prime_UTR_variant	16/16	1
ABCG2	ENST00000650821.1	c.1948T>C	p.Phe650Leu	missense_variant	17/17			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 12, 2024

The c.1948T>C (p.F650L) alteration is located in exon 16 (coding exon 15) of the ABCG2 gene. This alteration results from a T to C substitution at nucleotide position 1948, causing the phenylalanine (F) at amino acid position 650 to be replaced by a leucine (L). 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	0.44
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.98	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Benign	0.59	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.66		Loss of loop (P = 0.0512);
MVP		0.61
MPC		0.033
ClinPred		0.63	D
GERP RS		3.2
Varity_R		0.28

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: chr4-89013406; COSMIC: COSV52945565;