rs1801555

Positions:

• chr1-94001103-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.76

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]

ACMG classification

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	UniProt
ABCA4	NM_000350.3	c.6285T>C	p.Asp2095=	splice_region_variant, synonymous_variant	46/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.6063T>C	p.Asp2021=	splice_region_variant, synonymous_variant	45/49

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40724 AN: 151848 Hom.: 9717 Cov.: 32

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

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.: 34 AF XY: 0.133 AC XY: 96606 AN XY: 726550

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.: 32 AF XY: 0.263 AC XY: 19512 AN XY: 74290

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:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:2 Other:1

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

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

Other links and lift over

dbSNP: rs1801555; hg19: chr1-94466659; COSMIC: COSV64670821; COSMIC: COSV64670821;