1-94001046-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000350.3(ABCA4):c.6342G>A(p.Val2114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,078 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
ABCA4
NM_000350.3 synonymous
NM_000350.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.552
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-94001046-C-T is Pathogenic according to our data. Variant chr1-94001046-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94001046-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94001046-C-T is described in Lovd as [Pathogenic]. Variant chr1-94001046-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.6342G>A | p.Val2114= | synonymous_variant | 46/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.6120G>A | p.Val2040= | synonymous_variant | 45/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.6342G>A | p.Val2114= | synonymous_variant | 46/50 | 1 | NM_000350.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251420Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135878
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change affects codon 2114 of the ABCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCA4 protein. This variant is present in population databases (rs61748520, gnomAD 0.004%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662, 28041643). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99452). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 29, 2016 | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous c.6342G>A variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Stargardt disease. The presence of this variant in combination with a likely pathogenic variant increases the likelihood that the c.6342G>A variant is pathogenic. This variant has been identified in 0.001804% (5/277140) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61748520). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies with keratinocytes from a patient with the variant in the heterozygous state provide some evidence that the c.6342G>A variant may impact protein function by creating a premature donor splice site, causing exon skipping of Exon 46 (PMID: 23918662). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the c.6342G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PM3_Supporting (Richards 2015). - |
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
ABCA4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 03, 2023 | The ABCA4 c.6342G>A variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the compound heterozygous state in patients with Stargardt disease, and functional studies support its pathogenicity (Braun et al. 2013. PubMed ID: 23918662; Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94466602-C-T). This variant is interpreted as likely pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 24, 2018 | - - |
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 08, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
DS_DL_spliceai
Position offset: -44
Find out detailed SpliceAI scores and Pangolin per-transcript scores at