rs756090687
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_015404.4(WHRN):c.1547C>T(p.Thr516Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,856 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 Uncertain significance (★★).
Frequency
Consequence
NM_015404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251396Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135864
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727220
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Thr516Ile variant in DFNB31 has not been previously reported in individual s with hearing loss, but has been identified in 1/16512 of South Asian chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). T he threonine (Thr) at position 1547 is not highly conserved in mammals or evolut ionary distant species, and one mammal (Alpaca) has an Isoleucine (Ile) at this position, raising the possibility that this change at this position may be toler ated. Additional computational prediction tools do not provide strong support fo r or against an impact to the protein. In summary, the clinical significance of the p.Thr516Ile variant is uncertain. -
not provided Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 228560). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. This variant is present in population databases (rs756090687, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 516 of the WHRN protein (p.Thr516Ile). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at