rs2734715
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2
The NM_000391.4(TPP1):c.185C>T(p.Ser62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,614,002 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S62T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.185C>T | p.Ser62Leu | missense_variant | 3/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.185C>T | p.Ser62Leu | missense_variant | 3/13 | 1 | NM_000391.4 | P1 | |
ENST00000545572.1 | n.31G>A | non_coding_transcript_exon_variant | 1/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00509 AC: 774AN: 152126Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00144 AC: 362AN: 251354Hom.: 4 AF XY: 0.00102 AC XY: 139AN XY: 135864
GnomAD4 exome AF: 0.000557 AC: 814AN: 1461758Hom.: 6 Cov.: 31 AF XY: 0.000480 AC XY: 349AN XY: 727190
GnomAD4 genome ? AF: 0.00512 AC: 779AN: 152244Hom.: 5 Cov.: 32 AF XY: 0.00500 AC XY: 372AN XY: 74438
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2022 | Variant summary: TPP1 c.185C>T (p.Ser62Leu) results in a non-conservative amino acid change in 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 0.0014 in 251354 control chromosomes, predominantly at a frequency of 0.019 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9.7 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 African or African-American origin. To our knowledge, no penetrant association of c.185C>T in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating its impact on protein function have 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. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 24, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Neuronal ceroid lipofuscinosis 2 Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as 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 | Aug 13, 2021 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 11, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at