rs1801574

Positions:

Variant summary

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

The NM_000350.3(ABCA4):c.5682G>C(p.Leu1894Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,792 control chromosomes in the GnomAD database, including 46,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1894L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.23 ( 4307 hom., cov: 32)

Exomes 𝑓: 0.24 ( 42197 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 0.299

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:

ABCA4 (HGNC:):

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=-0.49).

BP6

Variant 1-94010832-C-G is Benign according to our data. Variant chr1-94010832-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 99396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94010832-C-G is described in Lovd as [Benign]. Variant chr1-94010832-C-G is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=0.299 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.5682G>C	p.Leu1894Leu	synonymous_variant	40/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.5460G>C	p.Leu1820Leu	synonymous_variant	39/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.5682G>C	p.Leu1894Leu	synonymous_variant	40/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000465352.1 linkuse as main transcript	n.98G>C		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35536

AN:

151902

Hom.:

4296

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.194

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.213

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.217

GnomAD3 exomes

AF:

0.216

AC:

54210

AN:

251178

Hom.:

6260

AF XY:

0.214

AC XY:

29045

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.249

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.239

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.214

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.229

GnomAD4 exome

AF:

0.237

AC:

346195

AN:

1461772

Hom.:

42197

Cov.:

AF XY:

0.234

AC XY:

170450

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.182

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.136

Gnomad4 SAS exome

AF:

0.152

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.250

Gnomad4 OTH exome

AF:

0.223

GnomAD4 genome

AF:

0.234

AC:

35595

AN:

152020

Hom.:

4307

Cov.:

AF XY:

0.229

AC XY:

16984

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.250

Gnomad4 AMR

AF:

0.192

Gnomad4 ASJ

AF:

0.246

Gnomad4 EAS

AF:

0.130

Gnomad4 SAS

AF:

0.145

Gnomad4 FIN

AF:

0.213

Gnomad4 NFE

AF:

0.252

Gnomad4 OTH

AF:

0.220

Alfa

AF:

0.242

Hom.:

3457

Bravo

AF:

0.233

Asia WGS

AF:

0.152

AC:

531

AN:

3478

EpiCase

AF:

0.250

EpiControl

AF:

0.250

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Retinitis Pigmentosa, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Age related macular degeneration 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

ABCA4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cone-Rod Dystrophy, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa 19

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cone-rod dystrophy 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Macular degeneration

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

2.7

DANN

Benign

0.73

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