11-119156387-G-T

Variant names:

• chr11-119156387-G-T
• rs1948263947
• NM_022169.5:c.745G>T

Variant summary

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

The NM_022169.5(ABCG4):​c.745G>T​(p.Gly249Trp) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
• Consequence: ABCG4 NM_022169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99

Genes affected

ABCG4 (HGNC:13884): (ATP binding cassette subfamily G member 4) The protein encoded by this gene is a member of the ATP-binding cassette (ABC) transporter superfamily. 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). The encoded protein is a member of the White subfamily and plays an important role in cellular cholesterol homeostasis. This protein functions as either a homodimer or as a heterodimer with another ABC subfamily protein such as ABCG1. [provided by RefSeq, Jan 2017]

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 rank	MANE	Protein	UniProt
ABCG4	NM_022169.5	c.745G>T	p.Gly249Trp	missense_variant	Exon 7 of 15	ENST00000619701.5	NP_071452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG4	ENST00000619701.5	c.745G>T	p.Gly249Trp	missense_variant	Exon 7 of 15	1	NM_022169.5	ENSP00000481728.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.745G>T (p.G249W) alteration is located in exon 7 (coding exon 6) of the ABCG4 gene. This alteration results from a G to T substitution at nucleotide position 745, causing the glycine (G) at amino acid position 249 to be replaced by a tryptophan (W). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Benign	0.0036	T
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Uncertain	0.76	T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.69
MutPred		0.53		Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);
MVP		0.73
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1948263947; hg19: chr11-119027097;