Genetic Variant ABCG4:p.Pro352Leu (chr11-119157001-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022169.5(ABCG4):c.1055C>T(p.Pro352Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,607,900 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.021 ( 103 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 90 hom. )

Consequence

ABCG4
NM_022169.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.55

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002490133).

BP6

Variant 11-119157001-C-T is Benign according to our data. Variant chr11-119157001-C-T is described in ClinVar as [Benign]. Clinvar id is 778565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG4	NM_022169.5 link	c.1055C>T	p.Pro352Leu	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.1055C>T	p.Pro352Leu	missense_variant	Exon 9 of 15	1	NM_022169.5	ENSP00000481728.1		Q9H172-1

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3127

AN:

152102

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0668

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00631

AC:

1539

AN:

244070

Hom.:

AF XY:

0.00504

AC XY:

664

AN XY:

131856

show subpopulations

Gnomad AFR exome

AF:

0.0667

Gnomad AMR exome

AF:

0.00634

Gnomad ASJ exome

AF:

0.00245

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000408

Gnomad FIN exome

AF:

0.0000939

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00759

GnomAD4 exome

AF:

0.00306

AC:

4450

AN:

1455680

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

2019

AN XY:

723954

show subpopulations

Gnomad4 AFR exome

AF:

0.0685

Gnomad4 AMR exome

AF:

0.00781

Gnomad4 ASJ exome

AF:

0.00215

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000411

Gnomad4 FIN exome

AF:

0.0000564

Gnomad4 NFE exome

AF:

0.00116

Gnomad4 OTH exome

AF:

0.00637

GnomAD4 genome

AF:

0.0205

AC:

3128

AN:

152220

Hom.:

103

Cov.:

AF XY:

0.0198

AC XY:

1473

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0666

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00530

Hom.:

Bravo

AF:

0.0250

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0584

AC:

257

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00730

AC:

886

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.69

.;.;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.14

N;N;N

PrimateAI

Benign

0.35

Sift4G

Benign

0.55

T;T;T

Polyphen

0.15

B;B;B

Vest4

0.13

MVP

0.70

ClinPred

0.035

GERP RS

4.7

Varity_R

0.069

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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