rs121908204
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000391.4(TPP1):c.380G>T(p.Arg127Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127Q) has been classified as Benign.
Frequency
Consequence
NM_000391.4 missense, splice_region
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 |
---|---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.380G>T | p.Arg127Leu | missense_variant, splice_region_variant | 4/13 | ENST00000299427.12 | NP_000382.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.380G>T | p.Arg127Leu | missense_variant, splice_region_variant | 4/13 | 1 | NM_000391.4 | ENSP00000299427 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251472Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 28, 2022 | This sequence change affects codon 127 of the TPP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TPP1 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908204, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. 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: "Benign"; Align-GVGD: "Class C25"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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