Genetic Variant ABCG4:p.Asn345Lys (chr11-119156981-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022169.5(ABCG4):c.1035C>G(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,612,868 control chromosomes in the GnomAD database, including 2,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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: 𝑓 0.068 ( 1164 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 1209 hom. )

Consequence

ABCG4
NM_022169.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.901

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038556159).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG4	NM_022169.5 link	c.1035C>G	p.Asn345Lys	missense_variant	Exon 9 of 15	ENST00000619701.5	NP_071452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG4	ENST00000619701.5 link	c.1035C>G	p.Asn345Lys	missense_variant	Exon 9 of 15	1	NM_022169.5	ENSP00000481728.1		Q9H172-1

Frequencies

GnomAD3 genomes

AF:

0.0679

AC:

10315

AN:

152000

Hom.:

1158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0284

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.0489

GnomAD3 exomes

AF:

0.0181

AC:

4532

AN:

249952

Hom.:

500

AF XY:

0.0133

AC XY:

1791

AN XY:

135062

show subpopulations

Gnomad AFR exome

AF:

0.244

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000362

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000478

Gnomad OTH exome

AF:

0.00822

GnomAD4 exome

AF:

0.00740

AC:

10812

AN:

1460750

Hom.:

1209

Cov.:

AF XY:

0.00640

AC XY:

4654

AN XY:

726688

show subpopulations

Gnomad4 AFR exome

AF:

0.257

Gnomad4 AMR exome

AF:

0.0147

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000650

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000304

Gnomad4 OTH exome

AF:

0.0175

GnomAD4 genome

AF:

0.0681

AC:

10352

AN:

152118

Hom.:

1164

Cov.:

AF XY:

0.0656

AC XY:

4878

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.235

Gnomad4 AMR

AF:

0.0284

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.0483

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.0831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.222

AC:

977

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.0221

AC:

2682

EpiCase

AF:

0.000873

EpiControl

AF:

0.000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0040

DANN

Benign

0.83

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.46

.;.;T

MetaRNN

Benign

0.0039

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;N

PrimateAI

Uncertain

0.51

Sift4G

Benign

0.81

T;T;T

Polyphen

0.072

B;B;B

Vest4

0.030

MutPred

0.45

Gain of ubiquitination at N345 (P = 0.0082);Gain of ubiquitination at N345 (P = 0.0082);Gain of ubiquitination at N345 (P = 0.0082);

ClinPred

0.0081

GERP RS

-11

Varity_R

0.047

gMVP

0.36

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over