rs760014795
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000370.3(TTPA):c.19del(p.Gln7SerfsTer64) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000874 in 1,486,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q7Q) has been classified as Likely benign.
Frequency
Consequence
NM_000370.3 frameshift
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.19del | p.Gln7SerfsTer64 | frameshift_variant | 1/5 | ENST00000260116.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTPA | ENST00000260116.5 | c.19del | p.Gln7SerfsTer64 | frameshift_variant | 1/5 | 1 | NM_000370.3 | P1 | |
TTPA | ENST00000521138.1 | n.47del | non_coding_transcript_exon_variant | 1/2 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151934Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000481 AC: 5AN: 104000Hom.: 0 AF XY: 0.0000503 AC XY: 3AN XY: 59688
GnomAD4 exome AF: 0.00000824 AC: 11AN: 1334904Hom.: 0 Cov.: 31 AF XY: 0.0000106 AC XY: 7AN XY: 659902
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151934Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74226
ClinVar
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 22, 2014 | The p.Gln7SerfsX64 variant in TTPA has not been previously reported in individuals with disease but has been identified in 0.016% (1/6134) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 7 and leads to a premature termination codon 64 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Homozygous or compound heterozygous loss of function variants in TTPA have been shown to cause ataxia with isolated vitamin E deficiency. In summary, this variant meets our criteria to be classified as pathogenic for ataxia with isolated vitamin E deficiency in an autosomal recessive manner. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Gln7Serfs*64) 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 (rs760014795, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with TTPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 208623). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at