11-119150033-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022169.5(ABCG4):c.68C>A(p.Thr23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ABCG4
NM_022169.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.825

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034467906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCG4	NM_022169.5 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 15	ENST00000619701.5	NP_071452.2
ABCG4	NM_001142505.1 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 15		NP_001135977.1
ABCG4	NM_001348191.2 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 15		NP_001335120.1
ABCG4	NM_001348192.2 link	c.-171C>A		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.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 15	1	NM_022169.5	ENSP00000481728.1	Q9H172-1
ABCG4	ENST00000622721.1 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 1 of 14	1		ENSP00000484289.1	Q9H172-1
ABCG4	ENST00000615496.4 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 15	2		ENSP00000479253.1	Q9H172-1
ABCG4	ENST00000524604.5 link	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 4	3		ENSP00000431915.1	E9PJ00

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

250386

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1461118

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.68C>A (p.T23K) alteration is located in exon 2 (coding exon 1) of the ABCG4 gene. This alteration results from a C to A substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 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

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.37

T;.;T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.82

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

.;T;.;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.34

N;.;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.15

.;N;.;.

REVEL

Benign

0.042

Sift

Benign

0.18

.;T;.;.

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.049

B;.;B;B

Vest4

0.23

MutPred

0.50

Gain of ubiquitination at T23 (P = 0.0051);Gain of ubiquitination at T23 (P = 0.0051);Gain of ubiquitination at T23 (P = 0.0051);Gain of ubiquitination at T23 (P = 0.0051);

MVP

0.38

ClinPred

0.053

GERP RS

0.52

Varity_R

0.077

gMVP

0.38

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

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