1-94113067-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000350.3(ABCA4):c.67-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000350.3 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA4 | ENST00000370225.4 | c.67-1G>C | splice_acceptor_variant, intron_variant | Intron 1 of 49 | 1 | NM_000350.3 | ENSP00000359245.3 | |||
ABCA4 | ENST00000649773.1 | c.67-1G>C | splice_acceptor_variant, intron_variant | Intron 1 of 18 | ENSP00000496882.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461694Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727152
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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This sequence change affects an acceptor splice site in intron 1 of the ABCA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Stargardt disease (PMID: 28118664, 29925512). ClinVar contains an entry for this variant (Variation ID: 236069). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28118664). For these reasons, this variant has been classified as Pathogenic. -
Severe early-childhood-onset retinal dystrophy Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at