NM_020458.4:c.1817A>G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_020458.4(TTC7A):āc.1817A>Gā(p.Lys606Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00298 in 1,613,908 control chromosomes in the GnomAD database, including 11 homozygotes. 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 Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00208 AC: 317AN: 152220Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00213 AC: 536AN: 251304Hom.: 3 AF XY: 0.00211 AC XY: 287AN XY: 135810
GnomAD4 exome AF: 0.00308 AC: 4499AN: 1461570Hom.: 10 Cov.: 31 AF XY: 0.00300 AC XY: 2180AN XY: 727088
GnomAD4 genome AF: 0.00208 AC: 317AN: 152338Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
TTC7A: BS2 -
PM3_Supporting, BS1 -
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Has been observed in with the S672P variant in multiple cases; in cases where phase was determined, it has been observed in cis with S672P in one individual with combined immunodeficiency with multiple intestinal atresias who harbored an another TTC7A variant in trans (Chen et al., 2013), and has also been observed in trans with the S672P in another individual with common variable immunodeficiency (Lawless et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28930861, 30443250, 23830146, 28808844, 27418642, 31814065) -
not specified Uncertain:1
Variant summary: TTC7A c.1817A>G (p.Lys606Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251304 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6-fold the estimated maximal expected allele frequency for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency Syndrome phenotype (0.00035), suggesting that the variant is benign. c.1817A>G has been reported in the literature in cis with c.2014T>C, p.Ser672Pro in at least one individual affected with Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA), who had a likely pathogenic variant (c.1000DelAAGT) in compound heterozygosity (e.g. Chen_2013). The variant has also been detected in several patients with early-onset inflammatory bowel disease (EOIBD) or inflammatory bowel disease (IBD), often occurring along with c.2014T>C, p.Ser672Pro (e.g. Kammermeier_2016, Petersen_2017, Ashton, 2020). In some cases, the variants were indicated to have been inherited as a complex allele, while in others, the phase was not reported. However, these two variants were also reported in trans in at least one individual affected by a mild form of Combined Variable Immunodeficiency Syndrome (CVID), suggesting that the variants could possibly be associated with a mild form of disease when found on separate alleles (e.g. Lawless_2017). The c.1817A>G and c.2014T>C variants were also reported in compound heterozygosity in an individual evaluated for IPEX (Immune Dysregulation, Polyendocrinopathy, Ebteropathy, X-Linked) Syndrome (e.g. Gambineri_2018). These findings do not provide unequivocal evidence for association of the variant with Severe Combined Immunodeficiency Syndrome. To the best of our knowledge, no experimental studies evaluating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Gastrointestinal defects and immunodeficiency syndrome 1 Uncertain:1
Criteria applied: PS4_MOD, PS3_SUP, PP3 -
TTC7A-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Multiple gastrointestinal atresias Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at