11-6616720-T-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000391.4(TPP1):c.827A>T(p.Asp276Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,862 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D276D) has been classified as Likely benign.
Frequency
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.827A>T | p.Asp276Val | missense_variant | 7/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.827A>T | p.Asp276Val | missense_variant | 7/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151890Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461854Hom.: 0 Cov.: 41 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152008Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 276 of the TPP1 protein (p.Asp276Val). This variant is present in population databases (rs763162812, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 22832778, 23266810, 25976102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 207581). 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 TPP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32488064, 33084218, 28792770, 25976102, 29655203, 19793312, 31440721, 23266810, 33377563, 31283065) - |
Neuronal ceroid lipofuscinosis 2 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Jan 20, 2020 | - - |
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at