rs140899003

Positions:

chr2-43819997-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_022436.3(ABCG5):c.1567A>G(p.Ile523Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,184 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 10 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.337

Variant links:

Genes affected

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. 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). This protein is a member of the White subfamily. The protein encoded by this gene functions as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG5 links:

ABCG5 (HGNC:):

ABCG5 links:

DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

DYNC2LI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011789948).

BP6

Variant 2-43819997-T-C is Benign according to our data. Variant chr2-43819997-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 502765.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=2}. Variant chr2-43819997-T-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG5	NM_022436.3 linkuse as main transcript	c.1567A>G	p.Ile523Val	missense_variant	11/13	ENST00000405322.8	NP_071881.1	Q9H222-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCG5	ENST00000405322.8 linkuse as main transcript	c.1567A>G	p.Ile523Val	missense_variant	11/13	1	NM_022436.3	ENSP00000384513.2	Q9H222-1
ABCG5	ENST00000486512.5 linkuse as main transcript	n.2088A>G		non_coding_transcript_exon_variant	7/9	1
ABCG5	ENST00000409962.1 linkuse as main transcript	n.1850A>G		non_coding_transcript_exon_variant	7/9	2
ABCG5	ENST00000644754.1 linkuse as main transcript	n.1951A>G		non_coding_transcript_exon_variant	8/10

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00641

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00170

AC:

428

AN:

251426

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00577

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00190

AC:

2784

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1363

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000939

Gnomad4 FIN exome

AF:

0.00562

Gnomad4 NFE exome

AF:

0.00203

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152296

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000891

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00641

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00124

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00169

AC:

205

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2024	Variant summary: ABCG5 c.1567A>G (p.Ile523Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 1614184 control chromosomes in the gnomAD database, including 10 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease (0.0019 vs 0.005), allowing no conclusion about variant significance. c.1567A>G has been reported in the literaturein at-least one patient suspected of partial lipodystrophy without strong evidence for causality (example: Johansen_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24503134, 32088153). ClinVar contains an entry for this variant (Variation ID: 502765). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2020	This variant is associated with the following publications: (PMID: 24503134) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ABCG5: BP4, BS2 -

Sitosterolemia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ABCG5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Sitosterolemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.54

DANN

Benign

0.19

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.62

.;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.64

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.12

N;.

REVEL

Benign

0.036

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;B

Vest4

0.016

MVP

0.39

MPC

0.060

ClinPred

0.0029

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.088

gMVP

0.32

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