rs1800717

chr1-93996198-A-G

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.6730-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,608,004 control chromosomes in the GnomAD database, including 7,710 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3492 hom., cov: 33)
  • Exomes 𝑓: 0.048 (4218 hom.)
• Consequence: ABCA4 NM_000350.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002718
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:2
• Conservation: PhyloP100: 0.779

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=-0.82).
• BP6: Variant 1-93996198-A-G is Benign according to our data. Variant chr1-93996198-A-G is described in ClinVar as [Benign]. Clinvar id is 99491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-93996198-A-G is described in Lovd as [Benign]. Variant chr1-93996198-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6730-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.6508-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6730-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21622 AN: 152132 Hom.: 3478 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.0652 AC: 16361 AN: 250840 Hom.: 1655 AF XY: 0.0582 AC XY: 7885 AN XY: 135592

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.0270

Gnomad SAS exome AF: 0.0498

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0633

GnomAD4 exome AF: 0.0481 AC: 70066 AN: 1455754 Hom.: 4218 Cov.: 30 AF XY: 0.0474 AC XY: 34334 AN XY: 724640

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.0504

Gnomad4 FIN exome AF: 0.00681

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0680

GnomAD4 genome AF: 0.142 AC: 21674 AN: 152250 Hom.: 3492 Cov.: 33 AF XY: 0.138 AC XY: 10257 AN XY: 74452

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.0847

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0407

Gnomad4 OTH AF: 0.124

Alfa AF: 0.0678 Hom.: 1503

Bravo AF: 0.160

Asia WGS AF: 0.0640 AC: 223 AN: 3478

EpiCase AF: 0.0497

EpiControl AF: 0.0504

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 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:1 Other:2

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -

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 12, 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

- -

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

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	-0.82
Cadd	Benign	4.0
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0040
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: rs1800717; hg19: chr1-94461754;