rs142486386
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA182517/MONDO:0019497/005
Frequency
Consequence
NM_005422.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.3097C>T | p.Arg1033Trp | missense_variant | 11/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.4054C>T | p.Arg1352Trp | missense_variant | 17/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.3097C>T | p.Arg1033Trp | missense_variant | 11/24 | 5 | NM_005422.4 | P4 | |
TECTA | ENST00000264037.2 | c.3097C>T | p.Arg1033Trp | missense_variant | 10/23 | 1 | P4 | ||
TECTA | ENST00000642222.1 | c.3097C>T | p.Arg1033Trp | missense_variant | 11/24 | A1 | |||
TECTA | ENST00000645008.1 | c.406C>T | p.Arg136Trp | missense_variant | 2/15 |
Frequencies
GnomAD3 genomes ? AF: 0.00140 AC: 212AN: 151920Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000346 AC: 87AN: 251328Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135826
GnomAD4 exome AF: 0.000200 AC: 293AN: 1461892Hom.: 1 Cov.: 32 AF XY: 0.000176 AC XY: 128AN XY: 727248
GnomAD4 genome ? AF: 0.00140 AC: 213AN: 152038Hom.: 2 Cov.: 32 AF XY: 0.00147 AC XY: 109AN XY: 74324
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 05, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 11, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2021 | Identified in a patient with hearing loss who was also heterozygous for the Q234R variant (Sloan-Heggen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26969326) - |
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2021 | Variant summary: TECTA c.3097C>T (p.Arg1033Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282672 control chromosomes, predominantly at a frequency of 0.0035 within the African or African-American subpopulation in the gnomAD database. This frequency is equal to the estimated maximal expected allele frequency of a pathogenic variant in TECTA causing Deafness, Autosomal Recessive 21 (0.0035 vs 0.0035), suggesting this may be a benign polymorphism. c.3097C>T has been reported in the literature in one individual affected with hearing loss (Sloan-Heggen_2016). The report does not provide unequivocal conclusions about association of the variant with Deafness, Autosomal Recessive 21. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=4), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 22, 2017 | p.Arg1033Trp in exon 10 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.3% (81/24020) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs142486386). - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 29, 2018 | The p.Arg1033Trp variant (rs142486386) has been reported in the medical literature in a single individual with a suspected diagnosis of non-syndromic hearing loss; however, inheritance and specific clinical information were not reported for this individual (Sloan-Heggen 2016). The p.Arg1033Trp variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.34% in the African population (identified in 81 out of 24,020 chromosomes), and is listed in the ClinVar database (Variant ID: 178538). The arginine at codon 1033 is highly conserved considering 11 species up to Tetraodon (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the TECTA protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). While the p.Arg1033Trp variant appears to be an ethnic specific polymorphism in the African population, the available evidence is insufficient to classify this variant with certainty. - |
Nonsyndromic genetic hearing loss Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Apr 29, 2019 | The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. - |
TECTA-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2021 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at