rs1428598791
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_ModeratePM1PP3
The NM_005422.4(TECTA):c.5839C>T(p.Arg1947Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_005422.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.5839C>T | p.Arg1947Cys | missense_variant | 20/24 | ENST00000392793.6 | NP_005413.2 | |
TBCEL-TECTA | NM_001378761.1 | c.6781C>T | p.Arg2261Cys | missense_variant | 26/30 | NP_001365690.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.5839C>T | p.Arg1947Cys | missense_variant | 20/24 | 5 | NM_005422.4 | ENSP00000376543 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152106Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727244
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | TECTA: PM2, PS4:Moderate - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27368438, 21520338, 31554319, 9590290, 16718611) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1947 of the TECTA protein (p.Arg1947Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 21520338). ClinVar contains an entry for this variant (Variation ID: 449555). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TECTA protein function. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 26, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1947Cy s variant in TECTA has been reported in 2 individual with hearing loss and segre gated with hearing loss in at least 1 family member, with possible additional se gregations mentioned, but not specified, in one publication (Hildebrand 2011, LM M data). It has been identified in 1/15010 European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 449555). Computational prediction t ools and conservation analysis suggest that the p.Arg1947Cys variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, while there is some suspicion for a pathogenic role, the c linical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS 4_Supporting, PP3, PM2. - |
TECTA-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2024 | The TECTA c.5839C>T variant is predicted to result in the amino acid substitution p.Arg1947Cys. This variant has previously been reported in an individual with autosomal dominant postlingual mid-frequency nonsyndromic hearing loss (Hildebrand et al. 2011. PubMed ID: 21520338). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at