rs104894934
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate
The NM_000330.4(RS1):c.325G>T(p.Gly109Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G109R) has been classified as Pathogenic.
Frequency
Consequence
NM_000330.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.325G>T | p.Gly109Trp | missense_variant, splice_region_variant | 4/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.229G>T | p.Gly77Trp | missense_variant, splice_region_variant | 2/4 | ||
CDKL5 | NM_001037343.2 | c.2797+1102C>A | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2797+1102C>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.325G>T | p.Gly109Trp | missense_variant, splice_region_variant | 4/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2797+1102C>A | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2797+1102C>A | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.816G>T | splice_region_variant, non_coding_transcript_exon_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly109 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326935, 28348004, 30652005, 31087526; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 98935). This missense change has been observed in individual(s) with clinical features of RS1-related conditions and/or retinoschisis (PMID: 10450864, 17296904, 28348004; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the RS1 protein (p.Gly109Trp). - |
not provided, no classification provided | literature only | Retina International | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at