rs200880556
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000391.4(TPP1):c.1664C>A(p.Ala555Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. A555T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.1664C>A | p.Ala555Asp | missense_variant | 13/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1664C>A | p.Ala555Asp | missense_variant | 13/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 0.000107 AC: 156AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.0000976 AC XY: 71AN XY: 727246
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 555 of the TPP1 protein (p.Ala555Asp). This variant is present in population databases (rs200880556, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 207597). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 02, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2018 | p.Ala555Asp (GCT>GAT): c.1664 C>A in exon 13 of the TPP1 gene (NM_000391.3)The Ala555Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ala555Asp in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged, non-polar Alanine residue is replaced by a negatively charged Aspartic acid residue. However, it alters a position in the protein that is not conserved across species. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala555Asp is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s). - |
Neuronal ceroid lipofuscinosis 2 Uncertain:1Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 10, 2020 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Uncertain significance and reported on 03-09-2021 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at