rs201663789
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_144991.3(TSPEAR):c.1528C>T(p.Arg510Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,614,046 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_144991.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSPEAR | NM_144991.3 | c.1528C>T | p.Arg510Ter | stop_gained | 9/12 | ENST00000323084.9 | |
TSPEAR | NM_001272037.2 | c.1324C>T | p.Arg442Ter | stop_gained | 10/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSPEAR | ENST00000323084.9 | c.1528C>T | p.Arg510Ter | stop_gained | 9/12 | 1 | NM_144991.3 | P1 | |
TSPEAR | ENST00000397916.1 | n.1483C>T | non_coding_transcript_exon_variant | 9/11 | 1 | ||||
TSPEAR-AS2 | ENST00000465978.1 | n.217-3903G>A | intron_variant, non_coding_transcript_variant | 5 | |||||
TSPEAR | ENST00000642437.1 | c.*1473C>T | 3_prime_UTR_variant, NMD_transcript_variant | 10/13 |
Frequencies
GnomAD3 genomes ? AF: 0.000131 AC: 20AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000342 AC: 86AN: 251220Hom.: 0 AF XY: 0.000390 AC XY: 53AN XY: 135828
GnomAD4 exome AF: 0.000258 AC: 377AN: 1461744Hom.: 0 Cov.: 32 AF XY: 0.000260 AC XY: 189AN XY: 727164
GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74462
ClinVar
Submissions by phenotype
Ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 9 of 12). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (92 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity (ClinVar; PMID:27736875). (P) 0803 - Low previous evidence of pathogenicity in unrelated individual(s). This variant has been reported as compound heterozygous in a patient with non-syndromic oligodontia (PMID:32112661). It has also been reported as a variant of uncertain significance in ClinVar. (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change creates a premature translational stop signal (p.Arg510*) in the TSPEAR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSPEAR are known to be pathogenic (PMID: 34042254). This variant is present in population databases (rs201663789, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of ectodermal dysplasia and/or non-syndromic oligodontia (PMID: 32112661; Invitae). ClinVar contains an entry for this variant (Variation ID: 504870). For these reasons, this variant has been classified as Pathogenic. - |
Tooth agenesis, selective, 10 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 20, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 02, 2017 | The p.Arg510X variant in TSPEAR has not been previously reported in individuals with hearing loss, but has been identified in 82/126654 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; db SNP rs201663789). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense v ariant leads to a premature termination codon at position 510, which is predicte d to lead to a truncated or absent protein. Truncating variants have been previo usly reported in two probands with hearing loss and segregated in two affected s iblings in one family (Delmaghani 2012, Sloan-Heggen 2016). However, a recent st udy has also associated truncating variants in TSPEAR, including the same varian t previously reported by Delmaghani et al, with autosomal recessive ectodermal d ysplasia without hearing loss (Peled 2016). Therefore, additional information i s needed to determine the gene-disease association and the disease mechanism. In summary, because the gene-disease association is unclear, the clinical signific ance of this variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at