Genetic Variant ABCG4:p.Ala5Val (chr11-119149979-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022169.5(ABCG4):c.14C>T(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,454,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ABCG4
NM_022169.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

Variant links:

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]

ABCG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.15063283).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCG4	NM_022169.5 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 15	ENST00000619701.5	NP_071452.2
ABCG4	NM_001142505.1 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 15		NP_001135977.1
ABCG4	NM_001348191.2 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 15		NP_001335120.1
ABCG4	NM_001348192.2 link	c.-225C>T		5_prime_UTR_variant	Exon 2 of 16		NP_001335121.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCG4	ENST00000619701.5 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 15	1	NM_022169.5	ENSP00000481728.1	Q9H172-1
ABCG4	ENST00000622721.1 link	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 14	1		ENSP00000484289.1	Q9H172-1
ABCG4	ENST00000615496.4 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 15	2		ENSP00000479253.1	Q9H172-1
ABCG4	ENST00000524604.5 link	c.14C>T	p.Ala5Val	missense_variant	Exon 2 of 4	3		ENSP00000431915.1	E9PJ00

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000410

AC:

AN:

244178

Hom.:

AF XY:

0.0000452

AC XY:

AN XY:

132790

show subpopulations

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:

0.0000581

Gnomad NFE exome

AF:

0.0000805

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1454742

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000211

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>T (p.A5V) 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 14, causing the alanine (A) at amino acid position 5 to be replaced by a valine (V). 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

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;T;T

Eigen

Benign

-0.022

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

.;T;.;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;L;L

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.78

.;N;.;.

REVEL

Benign

0.029

Sift

Uncertain

0.0080

.;D;.;.

Sift4G

Uncertain

0.059

T;D;T;T

Polyphen

0.098

B;.;B;B

Vest4

0.30

MutPred

0.26

Gain of methylation at K4 (P = 0.0301);Gain of methylation at K4 (P = 0.0301);Gain of methylation at K4 (P = 0.0301);Gain of methylation at K4 (P = 0.0301);

MVP

0.66

ClinPred

0.16

GERP RS

3.9

Varity_R

0.12

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over