rs201555289
Positions:
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).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 1 hom. )
Consequence
WHRN
NM_015404.4 missense
NM_015404.4 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 1.08
Genes affected
WHRN (HGNC:16361): (whirlin) This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05802259).
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00021 (306/1459294) while in subpopulation SAS AF= 0.000788 (68/86256). AF 95% confidence interval is 0.000638. There are 1 homozygotes in gnomad4_exome. There are 170 alleles in male gnomad4_exome subpopulation. Median coverage is 57. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WHRN | NM_015404.4 | c.2354C>T | p.Thr785Ile | missense_variant | 10/12 | ENST00000362057.4 | NP_056219.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WHRN | ENST00000362057.4 | c.2354C>T | p.Thr785Ile | missense_variant | 10/12 | 1 | NM_015404.4 | ENSP00000354623.3 |
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000300 AC: 75AN: 249902Hom.: 0 AF XY: 0.000385 AC XY: 52AN XY: 135158
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GnomAD4 exome AF: 0.000210 AC: 306AN: 1459294Hom.: 1 Cov.: 57 AF XY: 0.000234 AC XY: 170AN XY: 725982
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GnomAD4 genome 0.000204 AC: 31AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
Retinal dystrophy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;D;D
Sift4G
Benign
T;T;T
Polyphen
0.38, 0.28
.;B;B
Vest4
MVP
MPC
0.14
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at