rs141482368
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_000391.4(TPP1):āc.1033A>Cā(p.Met345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,613,344 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M345I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.1033A>C | p.Met345Leu | missense_variant | 8/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.1033A>C | p.Met345Leu | missense_variant | 8/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000499 AC: 76AN: 152174Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00162 AC: 408AN: 251448Hom.: 4 AF XY: 0.00215 AC XY: 292AN XY: 135896
GnomAD4 exome AF: 0.000880 AC: 1285AN: 1461052Hom.: 20 Cov.: 89 AF XY: 0.00128 AC XY: 930AN XY: 726856
GnomAD4 genome ? AF: 0.000492 AC: 75AN: 152292Hom.: 1 Cov.: 32 AF XY: 0.000738 AC XY: 55AN XY: 74476
ClinVar
Submissions by phenotype
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | TPP1: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2018 | This variant is associated with the following publications: (PMID: 30541466) - |
Neuronal ceroid lipofuscinosis 2 Benign:3
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2022 | Variant summary: TPP1 c.1033A>C (p.Met345Leu) results in a conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251448 control chromosomes, predominantly at a frequency of 0.013 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1033A>C has been reported in the literature in a heterozygous individual (non-informative genotype) reportedly affected with Neuronal Ceroid-Lipofuscinosis without evidence for causality (Sheth_2018). This report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at