rs17110761

chr1-94001851-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000350.3(ABCA4):c.6282+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,614,088 control chromosomes in the GnomAD database, including 6,526 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2073 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4453 hom.)
• Consequence: ABCA4 NM_000350.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004080
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.0610

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-94001851-C-T is Benign according to our data. Variant chr1-94001851-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 99443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94001851-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6282+7G>A		splice_region_variant, intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.6060+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6282+7G>A		splice_region_variant, intron_variant		1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.705G>A		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19386 AN: 152132 Hom.: 2075 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.0582

Gnomad SAS AF: 0.0705

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.0766 AC: 19243 AN: 251212 Hom.: 1218 AF XY: 0.0727 AC XY: 9870 AN XY: 135804

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0616

Gnomad SAS exome AF: 0.0715

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0668 AC: 97609 AN: 1461836 Hom.: 4453 Cov.: 32 AF XY: 0.0667 AC XY: 48520 AN XY: 727214

Gnomad4 AFR exome AF: 0.307

Gnomad4 AMR exome AF: 0.0553

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0508

Gnomad4 SAS exome AF: 0.0710

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.0594

Gnomad4 OTH exome AF: 0.0845

GnomAD4 genome AF: 0.127 AC: 19407 AN: 152252 Hom.: 2073 Cov.: 33 AF XY: 0.125 AC XY: 9287 AN XY: 74448

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.0785

Gnomad4 ASJ AF: 0.0974

Gnomad4 EAS AF: 0.0579

Gnomad4 SAS AF: 0.0692

Gnomad4 FIN AF: 0.0334

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0817 Hom.: 1024

Bravo AF: 0.139

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.0693

EpiControl AF: 0.0673

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2014	- -

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

- -

ABCA4-related disorder Benign:1

Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cone-Rod Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

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	-0.71
Cadd	Benign	0.37
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.036
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: rs17110761; hg19: chr1-94467407;