rs121917851
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000370.3(TTPA):c.400C>T(p.Arg134Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000564 in 1,612,366 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R134R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000370.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTPA | NM_000370.3 | c.400C>T | p.Arg134Ter | stop_gained | 3/5 | ENST00000260116.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTPA | ENST00000260116.5 | c.400C>T | p.Arg134Ter | stop_gained | 3/5 | 1 | NM_000370.3 | P1 | |
TTPA | ENST00000521138.1 | n.233-17453C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000398 AC: 6AN: 150644Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251282Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135814
GnomAD4 exome AF: 0.0000582 AC: 85AN: 1461722Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727156
GnomAD4 genome ? AF: 0.0000398 AC: 6AN: 150644Hom.: 0 Cov.: 33 AF XY: 0.0000272 AC XY: 2AN XY: 73474
ClinVar
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 19, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 08, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 24, 2018 | Variant summary: TTPA c.400C>T (p.Arg134X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 246084 control chromosomes (gnomAD). c.400C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia with Vitamin E Deficiency (Cavalier 1998, Euch-Fayache 2014, Elkamil 2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 07, 2022 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change creates a premature translational stop signal (p.Arg134*) in the TTPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). This variant is present in population databases (rs121917851, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 9463307, 12470185, 22696689, 25614784). ClinVar contains an entry for this variant (Variation ID: 9141). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12899840, 12470185, 25525159, 20301419, 9463307, 22696689, 24369383, 19566498, 25614784, 32979145, 31589614, 32928973) - |
Ataxia, Friedreich-like, with isolated vitamin E deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at