rs869320785

Variant names:

• chr1-94027417-G-A
• rs869320785
• NM_000350.3:c.4539+2028C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000350.3(ABCA4):​c.4539+2028C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000039 (0 hom., cov: 33)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.0590

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 Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 1-94027417-G-A is Pathogenic according to our data. Variant chr1-94027417-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 236116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94027417-G-A is described in Lovd as [Pathogenic]. Variant chr1-94027417-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94027417-G-A is described in Lovd as [Pathogenic]. Variant chr1-94027417-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.4539+2028C>T		intron_variant	Intron 30 of 49	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.4317+2028C>T		intron_variant	Intron 29 of 48		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.4539+2028C>T		intron_variant	Intron 30 of 49	1	NM_000350.3	ENSP00000359245.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 30 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236116). Studies have shown that this variant results in pseudoexon inclusion, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 29526278). For these reasons, this variant has been classified as Pathogenic. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with insertion of a 345 bp pseudoexon containing a stop codon, and the resulting transcript was subject to nonsense-mediated decay (Albert et al., 2018); This variant is associated with the following publications: (PMID: 26527198, 28118664, 23918662, 28771251, 29526278) -

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Severe early-childhood-onset retinal dystrophy Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein due to the insertion of a retina-specific 345-nt pseudoexon (predicted protein change: p.Arg1514Leufs*36) (PMID: 29526278). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (6 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times in Stargardt disease patients. Many of these patients have this variant in cis with c.302+68C>T (ClinVar, PMIDs: 32627976; 32307445; 25082829; 23918662). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, it was demonstrated this deep-intronic variant results in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs*36), likely due to the creation of exonic enhancers. This variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (PMID: 29526278). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The ABCA4 c.4539+2028C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PM3-S. Based on this evidence we have classified this variant as Pathogenic. -

Retinal dystrophy Pathogenic:2

Jul 16, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Jan 01, 2010

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 c.4539+2028C>T variant is predicted to interfere with splicing. This deep intronic variant has been reported in multiple individuals with Stargardt disease (see for examples: Table 1, Braun et al. 2013. PubMed ID: 23918662; Table S2, Lionel et al. 2017. PubMed ID: 28771251; Fadaie et al. 2021. PubMed ID: 34795310). RNA analysis of patient derived cells demonstrated that the c.4539+2028C>T variant causes the inclusion of a 345-nucleotide pseudo-exon (Albert et al. 2018. PubMed ID: 29526278; Huang et al. 2022. PubMed ID: 36209838). This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has been listed as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/236116/). Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869320785; hg19: chr1-94492973;