rs201555289
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_015404.4(WHRN):c.2354C>T(p.Thr785Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,611,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T785T) has been classified as Likely benign.
Frequency
Consequence
NM_015404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WHRN | NM_015404.4 | c.2354C>T | p.Thr785Ile | missense_variant | 10/12 | ENST00000362057.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WHRN | ENST00000362057.4 | c.2354C>T | p.Thr785Ile | missense_variant | 10/12 | 1 | NM_015404.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000204 AC: 31AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000300 AC: 75AN: 249902Hom.: 0 AF XY: 0.000385 AC XY: 52AN XY: 135158
GnomAD4 exome AF: 0.000210 AC: 306AN: 1459294Hom.: 1 Cov.: 57 AF XY: 0.000234 AC XY: 170AN XY: 725982
GnomAD4 genome ? AF: 0.000204 AC: 31AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 785 of the WHRN protein (p.Thr785Ile). This variant is present in population databases (rs201555289, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 45673). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2021 | In silico analysis supports that this missense variant does not alter 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 | Dec 20, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Thr785Ile varia nt in DFNB31 has not been reported in the literature nor previously identified b y our laboratory. Computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr785Ile variant ma y not impact the protein. In addition, this variant has been identified in 0.03% (3/8600) of European American chromosomes and 0.02% (1/4406) of African America n chromosomes in a broad population by the NHLBI Exome sequencing project (http: //evs.gs.washington.edu/EVS/; dbSNP rs201555289). In summary, computational ana lyses predictions, lack of conservation at this position, and the presence of th is variant in the general population support a more likely benign role, however additional data is needed to determine its clinical significance with certainty. - |
Autosomal recessive nonsyndromic hearing loss 31 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Usher syndrome type 2D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at