rs140567004
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001199799.2(ILDR1):c.1297C>T(p.Arg433Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R433Q) has been classified as Benign.
Frequency
Consequence
NM_001199799.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ILDR1 | NM_001199799.2 | c.1297C>T | p.Arg433Trp | missense_variant | 7/8 | ENST00000344209.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ILDR1 | ENST00000344209.10 | c.1297C>T | p.Arg433Trp | missense_variant | 7/8 | 1 | NM_001199799.2 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000506 AC: 77AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000267 AC: 67AN: 250626Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135568
GnomAD4 exome AF: 0.000199 AC: 291AN: 1461742Hom.: 0 Cov.: 40 AF XY: 0.000197 AC XY: 143AN XY: 727160
GnomAD4 genome ? AF: 0.000512 AC: 78AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74496
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 42 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 22, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 21, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 01, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 433 of the ILDR1 protein (p.Arg433Trp). This variant is present in population databases (rs140567004, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ILDR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 504596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 17, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg433Trp var iant in ILDR1 has not been previously reported in patients with hearing loss. It has been identified in 0.2% (19/10134) of African chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140567004); ho wever, its frequency is not high enough to rule out a pathogenic role. Computati onal prediction tools and conservation analysis suggest that the p.Arg433Trp var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, while the clinical significance of the p.Arg433Trp variant is uncertain, available data suggest that it is more likely to be benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at