chr8-63066035-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000370.3(TTPA):c.421G>A(p.Glu141Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,758 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). Synonymous variant affecting the same amino acid position (i.e. E141E) has been classified as Likely benign.
Frequency
Consequence
NM_000370.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTPA | NM_000370.3 | c.421G>A | p.Glu141Lys | missense_variant | 3/5 | ENST00000260116.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTPA | ENST00000260116.5 | c.421G>A | p.Glu141Lys | missense_variant | 3/5 | 1 | NM_000370.3 | P1 | |
TTPA | ENST00000521138.1 | n.233-17432G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152004Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251346Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135842
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461754Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727168
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152004Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74232
ClinVar
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:1Uncertain:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2021 | Variant summary: TTPA c.421G>A (p.Glu141Lys) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, several structural studies predict this disrupts the hydrogen bond between the highly conserved E141 on helix 9 (residues 129143) and Y73, and this helix is a central building block of the CRAL-TRIO fold forming one wall of the tocopherol-binding cavity (Meier_2003, Min_2003, Bromley_2013), suggesting the important role of this variant in protein function. The variant allele was found at a frequency of 2.4e-05 in 251346 control chromosomes (gnomAD). c.421G>A has been reported in the literature in individuals affected with Ataxia With Vitamin E Deficiency, including one homozygote (Cavalier_1998, Ames_2002). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in mild kinetic impairment in their ability to catalyze tocopherol transfer (Morley_2004, Morley_2008). 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 VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at