rs202044972
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020458.4(TTC7A):c.2515G>A(p.Ala839Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,650 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 Uncertain significance (★★).
Frequency
Consequence
NM_020458.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTC7A | ENST00000319190.11 | c.2515G>A | p.Ala839Thr | missense_variant | Exon 20 of 20 | 2 | NM_020458.4 | ENSP00000316699.5 | ||
ENSG00000273269 | ENST00000422269.1 | n.*656-7724C>T | intron_variant | Intron 8 of 8 | 2 | ENSP00000476793.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250996Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135772
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461342Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 726998
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74478
ClinVar
Submissions by phenotype
Gastrointestinal defects and immunodeficiency syndrome 1 Pathogenic:1
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not specified Uncertain:1
Variant summary: TTC7A c.2515G>A (p.Ala839Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250996 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2515G>A has been reported in the literature in an individual affected with Tricho-hepato-enteric syndrome with a non-informative genotype (pathogenicity of the second allele is uncertain) (example: Neves_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Multiple gastrointestinal atresias Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 839 of the TTC7A protein (p.Ala839Thr). This variant is present in population databases (rs202044972, gnomAD 0.003%). This missense change has been observed in individual(s) with gastrointestinal defects and immunodeficiency syndrome (PMID: 29174094). ClinVar contains an entry for this variant (Variation ID: 440891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTC7A protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at