rs144971707
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_020458.4(TTC7A):c.974G>A(p.Arg325Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020458.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000519 AC: 79AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000247 AC: 62AN: 251184Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135810
GnomAD4 exome AF: 0.000121 AC: 177AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92AN XY: 727210
GnomAD4 genome AF: 0.000519 AC: 79AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 34AN XY: 74286
ClinVar
Submissions by phenotype
Gastrointestinal defects and immunodeficiency syndrome 1 Uncertain:2
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The TTC7A c.974G>A (p.Arg325Gln) missense variant has been reported in a homozygous state in two individuals with features of gastrointestinal defects and immunodeficiency syndrome in the medical literature (PMID: 31787977; 32531373). The highest frequency of this allele in the Genome Aggregation Database is 0.001498 in the African/African American population (version 3.1.2). Functional studies conducted in patient cells demonstrate that this variant results in reduced protein expression and function (PMID: 31787977). The c.974G>A variant was detected in trans with a variant of uncertain significance in this proband. Based on the available evidence, the c.974G>A (p.Arg325Gln) variant is classified as a variant of uncertain significance for gastrointestinal defects and immunodeficiency syndrome. -
not specified Uncertain:1
Variant summary: TTC7A c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the Tetratricopeptide repeat protein 7, N-terminal domain (IPR045819) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251184 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency (0.00025 vs 0.00035), allowing no conclusion about variant significance. However, the frequency in the African subpopulation (0.0018) is much higher than estimated from disease prevalence. c.974G>A has been reported in the literature as a homozygous genotype in at-least two affected individuals with features of Primary Immunodeficiency who underwent a comprehensive NGS panel based diagnostic workup (example, Fusaro_2021, El-Daher_2019). At-least one of these two individuals reported a North African ethnicity (Fusaro_2021). One of these patients presented with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO) (El-Daher_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (El-Daher_2019). The authors reported the mutant protein was unstable in B and T lymphoblasts leading to partial degradation, unable to stabilize subunits like EFR3 leading to low levels of EFR3 in B-cells and affected the ability of the mutant protein to regulate DNA accessibility, DNA stability and chromatin condensation. One clinical diagnostic laboratory has 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 VUS-possibly pathogenic. -
not provided Uncertain:1
PS3, PM3, BS1 -
Multiple gastrointestinal atresias Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at