11-119150066-C-T

Variant names:

• chr11-119150066-C-T
• rs1198810776
• NM_022169.5:c.101C>T

Variant summary

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

The NM_022169.5(ABCG4):​c.101C>T​(p.Thr34Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ABCG4 NM_022169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24021256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG4	NM_022169.5	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 15	ENST00000619701.5	NP_071452.2
ABCG4	NM_001142505.1	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 15		NP_001135977.1
ABCG4	NM_001348191.2	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 15		NP_001335120.1
ABCG4	NM_001348192.2	c.-138C>T		5_prime_UTR_variant	Exon 2 of 16		NP_001335121.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG4	ENST00000619701.5	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 15	1	NM_022169.5	ENSP00000481728.1
ABCG4	ENST00000622721.1	c.101C>T	p.Thr34Ile	missense_variant	Exon 1 of 14	1		ENSP00000484289.1
ABCG4	ENST00000615496.4	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 15	2		ENSP00000479253.1
ABCG4	ENST00000524604.5	c.101C>T	p.Thr34Ile	missense_variant	Exon 2 of 4	3		ENSP00000431915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251202 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101C>T (p.T34I) alteration is located in exon 2 (coding exon 1) of the ABCG4 gene. This alteration results from a C to T substitution at nucleotide position 101, causing the threonine (T) at amino acid position 34 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	.;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.031	.;D;.;.
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.26
MutPred		0.44		Loss of glycosylation at T34 (P = 0.0167);Loss of glycosylation at T34 (P = 0.0167);Loss of glycosylation at T34 (P = 0.0167);Loss of glycosylation at T34 (P = 0.0167);
MVP		0.53
ClinPred		0.46	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1198810776; hg19: chr11-119020776;