rs61750138
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The ENST00000370225.4(ABCA4):c.4253+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
ENST00000370225.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4253+5G>T | splice_donor_5th_base_variant, intron_variant | ENST00000370225.4 | NP_000341.2 | |||
ABCA4 | XM_047416704.1 | c.4031+5G>T | splice_donor_5th_base_variant, intron_variant | XP_047272660.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4253+5G>T | splice_donor_5th_base_variant, intron_variant | 1 | NM_000350.3 | ENSP00000359245 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727140
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change falls in intron 28 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61750138, gnomAD 0.0009%). This variant has been observed in individuals with Stargardt disease (PMID: 9973280, 28041643; Invitae). ClinVar contains an entry for this variant (Variation ID: 99267). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29162642). This variant disrupts the c.4253+5G nucleotide in the ABCA4 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10958763, 11385708, 28041643, 29162642). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2024 | Published functional studies demonstrate significant aberrant splicing with skipping of exon 28 (PMID: 29162642); Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25525159, 35120629, 31964843, 36284460, 22247458, 9666097, 9973280, 23499370, 24550365, 28041643, 32581362, 29162642) - |
not provided, no classification provided | literature only | Retina International | - | - - |
Severe early-childhood-onset retinal dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
ABCA4-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The ABCA4 c.4253+5G>T variant is predicted to interfere with splicing. This variant has been reported in individuals with Stargardt disease (Lewis et al. 1999. PubMed ID: 9973280; Supplemental data, Turro et al. 2020. PubMed ID: 32581362; Table S3, Suga et al. 2022. PubMed ID: 36284460). A functional study using a midigene splicing assay showed that this variant causes a significant decrease in correctly spliced mRNA (Sangermano et al. 2018. PubMed ID: 29162642). Alternate variants of this nucleotide and an adjacent nucleotide (c.4253+5G>A and c.4253+4C>T) have been reported in individuals with Stargardt disease (Rivera et al. 2000. PubMed ID: 10958763; Ozgul et al. 2004. PubMed ID: 15108289). This c.4253+5G>T variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 06, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at