rs4147857

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000350.3(ABCA4):c.5814A>G(p.Leu1938Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,452 control chromosomes in the GnomAD database, including 29,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3167 hom., cov: 31)

Exomes 𝑓: 0.19 ( 26471 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: -0.130

Variant links:

Genes affected

ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated 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 intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-94008772-T-C is Benign according to our data. Variant chr1-94008772-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 99407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94008772-T-C is described in Lovd as [Benign]. Variant chr1-94008772-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.13 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3 link	c.5814A>G	p.Leu1938Leu	synonymous_variant	Exon 41 of 50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	NM_001425324.1 link	c.5592A>G	p.Leu1864Leu	synonymous_variant	Exon 40 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 link	c.5814A>G	p.Leu1938Leu	synonymous_variant	Exon 41 of 50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 link	n.230A>G		non_coding_transcript_exon_variant	Exon 2 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30566

AN:

151826

Hom.:

3152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.188

GnomAD3 exomes

AF:

0.190

AC:

47731

AN:

251474

Hom.:

4842

AF XY:

0.184

AC XY:

25043

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.177

Gnomad NFE exome

AF:

0.192

Gnomad OTH exome

AF:

0.189

GnomAD4 exome

AF:

0.188

AC:

274047

AN:

1461508

Hom.:

26471

Cov.:

AF XY:

0.186

AC XY:

134952

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.248

Gnomad4 AMR exome

AF:

0.241

Gnomad4 ASJ exome

AF:

0.207

Gnomad4 EAS exome

AF:

0.136

Gnomad4 SAS exome

AF:

0.135

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.190

Gnomad4 OTH exome

AF:

0.185

GnomAD4 genome

AF:

0.202

AC:

30633

AN:

151944

Hom.:

3167

Cov.:

AF XY:

0.199

AC XY:

14746

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.208

Gnomad4 ASJ

AF:

0.214

Gnomad4 EAS

AF:

0.131

Gnomad4 SAS

AF:

0.131

Gnomad4 FIN

AF:

0.174

Gnomad4 NFE

AF:

0.192

Gnomad4 OTH

AF:

0.194

Alfa

AF:

0.195

Hom.:

6848

Bravo

AF:

0.208

Asia WGS

AF:

0.161

AC:

561

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.189

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3Other:1

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis Pigmentosa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt Disease, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Age related macular degeneration 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Severe early-childhood-onset retinal dystrophy

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-Rod Dystrophy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 19

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 3

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Macular degeneration

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.4

DANN

Benign

0.52

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