rs397515378
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000370.3(TTPA):c.487del(p.Trp163GlyfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
TTPA
NM_000370.3 frameshift
NM_000370.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.64
Genes affected
TTPA (HGNC:12404): (alpha tocopherol transfer protein) This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 8-63065968-CA-C is Pathogenic according to our data. Variant chr8-63065968-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-63065968-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTPA | NM_000370.3 | c.487del | p.Trp163GlyfsTer13 | frameshift_variant | 3/5 | ENST00000260116.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTPA | ENST00000260116.5 | c.487del | p.Trp163GlyfsTer13 | frameshift_variant | 3/5 | 1 | NM_000370.3 | P1 | |
TTPA | ENST00000521138.1 | n.233-17366del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251316Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135818
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GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461772Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 36AN XY: 727186
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 24, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2019 | Variant summary: TTPA c.487delT (p.Trp163GlyfsX13) 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 2.9e-05 in 277072 control chromosomes (gnomAD). c.487delT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia with Vitamin E Deficiency, which vitamin E levels were significantly decreased (<10%) (Hentati 1996, Cavalier 1998, Becker 2016). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 26, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 29, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Trp163Glyfs*13) 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 (rs748164236, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with vitamin E deficiency (PMID: 8602747, 9463307, 12907280, 15300460, 27274910). This variant is also known as 485delT, 486delT. ClinVar contains an entry for this variant (Variation ID: 188951). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Ataxia, Friedreich-like, with isolated vitamin E deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at