rs281865377
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000350.3(ABCA4):βc.4537delβ(p.Gln1513ArgfsTer13) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000716 in 1,397,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. Q1513Q) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000350.3 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA4 | NM_000350.3 | c.4537del | p.Gln1513ArgfsTer13 | frameshift_variant, splice_region_variant | 30/50 | ENST00000370225.4 | |
ABCA4 | XM_047416704.1 | c.4315del | p.Gln1439ArgfsTer13 | frameshift_variant, splice_region_variant | 29/49 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.4537del | p.Gln1513ArgfsTer13 | frameshift_variant, splice_region_variant | 30/50 | 1 | NM_000350.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000716 AC: 10AN: 1397456Hom.: 0 Cov.: 31 AF XY: 0.00000871 AC XY: 6AN XY: 689248
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438096). This premature translational stop signal has been observed in individuals with ABCA4-related retinal dystrophies (PMID: 19028736, 20696155). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln1513Argfs*13) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 08, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32581362, 32467599, 19959634, 23755871, 20696155, 28041643, 20960624) - |
Macular dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 22, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at