rs1801555

Positions:

chr1-94001103-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000350.3(ABCA4):c.6285T>C(p.Asp2095=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,612,464 control chromosomes in the GnomAD database, including 28,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 9736 hom., cov: 32)

Exomes 𝑓: 0.13 ( 18903 hom. )

Consequence

ABCA4
NM_000350.3 splice_region, synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 1.76

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 1-94001103-A-G is Benign according to our data. Variant chr1-94001103-A-G is described in ClinVar as [Benign]. Clinvar id is 99444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94001103-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.76 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 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.6285T>C	p.Asp2095=	splice_region_variant, synonymous_variant	46/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.6063T>C	p.Asp2021=	splice_region_variant, synonymous_variant	45/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.6285T>C	p.Asp2095=	splice_region_variant, synonymous_variant	46/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40724

AN:

151848

Hom.:

9717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.184

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.249

GnomAD3 exomes

AF:

0.158

AC:

39517

AN:

250446

Hom.:

5553

AF XY:

0.151

AC XY:

20451

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.665

Gnomad AMR exome

AF:

0.0987

Gnomad ASJ exome

AF:

0.193

Gnomad EAS exome

AF:

0.149

Gnomad SAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.0737

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.133

AC:

194137

AN:

1460498

Hom.:

18903

Cov.:

AF XY:

0.133

AC XY:

96606

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.676

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.195

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.166

Gnomad4 FIN exome

AF:

0.0755

Gnomad4 NFE exome

AF:

0.114

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.268

AC:

40791

AN:

151966

Hom.:

9736

Cov.:

AF XY:

0.263

AC XY:

19512

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.646

Gnomad4 AMR

AF:

0.149

Gnomad4 ASJ

AF:

0.184

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.164

Gnomad4 FIN

AF:

0.0723

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.251

Alfa

AF:

0.168

Hom.:

1108

Bravo

AF:

0.292

Asia WGS

AF:

0.209

AC:

730

AN:

3478

EpiCase

AF:

0.131

EpiControl

AF:

0.132

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2011	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. -

Retinitis Pigmentosa, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Cone-Rod Dystrophy, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Macular degeneration

Benign:1

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

-0.46

CADD

Benign

0.30

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