rs61751396
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000350.3(ABCA4):c.2588-12C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,606,312 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0023 ( 11 hom. )
Consequence
ABCA4
NM_000350.3 splice_polypyrimidine_tract, intron
NM_000350.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00002411
2
Clinical Significance
Conservation
PhyloP100: -0.215
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 Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 1-94051710-G-C is Benign according to our data. Variant chr1-94051710-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99148.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, not_provided=1, Uncertain_significance=1}. Variant chr1-94051710-G-C is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 11 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.2588-12C>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000370225.4 | |||
ABCA4 | XM_047416704.1 | c.2366-12C>G | splice_polypyrimidine_tract_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.2588-12C>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000350.3 | P1 | |||
ABCA4 | ENST00000649773.1 | c.2366-12C>G | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes AF: 0.00177 AC: 269AN: 152194Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00219 AC: 549AN: 250902Hom.: 3 AF XY: 0.00221 AC XY: 300AN XY: 135610
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GnomAD4 exome AF: 0.00226 AC: 3293AN: 1454000Hom.: 11 Cov.: 28 AF XY: 0.00221 AC XY: 1602AN XY: 724014
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GnomAD4 genome AF: 0.00177 AC: 269AN: 152312Hom.: 1 Cov.: 33 AF XY: 0.00167 AC XY: 124AN XY: 74474
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:4Other:1
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | ABCA4: BP4, BS2 - |
not provided, no classification provided | literature only | Retina International | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
ABCA4-related disorder Uncertain:1
Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 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. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at