chr1-204406261-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_032833.5(PPP1R15B):c.1973G>A(p.Arg658His) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R658C) has been classified as Pathogenic.
Frequency
Consequence
NM_032833.5 missense
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 |
---|---|---|---|---|---|---|---|
PPP1R15B | NM_032833.5 | c.1973G>A | p.Arg658His | missense_variant | 2/2 | ENST00000367188.5 | |
PPP1R15B | XM_005245551.6 | c.1920+3231G>A | intron_variant | ||||
PPP1R15B | XM_047432518.1 | c.1920+3231G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPP1R15B | ENST00000367188.5 | c.1973G>A | p.Arg658His | missense_variant | 2/2 | 1 | NM_032833.5 | P1 | |
PPP1R15B-AS1 | ENST00000443515.1 | n.146+28266C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251392Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727204
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 658 of the PPP1R15B protein (p.Arg658His). This variant is present in population databases (rs759466766, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PPP1R15B-related conditions. ClinVar contains an entry for this variant (Variation ID: 807902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPP1R15B protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at