rs146175803
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_005422.4(TECTA):āc.2657A>Gā(p.Asn886Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005422.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.2657A>G | p.Asn886Ser | missense_variant | Exon 10 of 24 | 5 | NM_005422.4 | ENSP00000376543.1 | ||
TECTA | ENST00000264037.2 | c.2657A>G | p.Asn886Ser | missense_variant | Exon 9 of 23 | 1 | ENSP00000264037.2 | |||
TECTA | ENST00000642222.1 | c.2657A>G | p.Asn886Ser | missense_variant | Exon 10 of 24 | ENSP00000493855.1 | ||||
TECTA | ENST00000645008.1 | c.-38A>G | upstream_gene_variant | ENSP00000496274.1 |
Frequencies
GnomAD3 genomes AF: 0.000605 AC: 92AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000475 AC: 119AN: 250476Hom.: 0 AF XY: 0.000436 AC XY: 59AN XY: 135330
GnomAD4 exome AF: 0.000836 AC: 1221AN: 1460664Hom.: 1 Cov.: 31 AF XY: 0.000807 AC XY: 586AN XY: 726478
GnomAD4 genome AF: 0.000604 AC: 92AN: 152298Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36AN XY: 74470
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Reported in published literature in unrelated individuals with suspected autosomal recessive nonsyndromic hearing loss, each with a second TECTA variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 27068579, 29196752); Reported in published literature in association with autosomal dominant non-syndromic hearing loss in one family, where it was identified in cis with a splicing variant in the TECTA gene in all affected individuals tested (PMID: 21520338); In silico analysis indicates that this missense variant does not alter protein structure/function; Within the ZA, zonadhesin and VWFD2, von Willebrand factor type D2 domains (PMID: 21520338, 31554319, 9590290); This variant is associated with the following publications: (PMID: 25262649, 22995349, 27368438, 30245029, 29196752, 21520338, 27068579, 31554319, 9590290) -
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Autosomal recessive nonsyndromic hearing loss 21 Uncertain:2
A heterozygous missense variant, NM_005422.2(TECTA):c.2657A>G, has been identified in exon 9 of 23 of the TECTA gene. The variant is predicted to result in a minor amino acid change from asparagine to serine at position 886 of the protein (NP_005413.2(TECTA):p.Asn886Ser). The asparagine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the VWFD 2 functional domain. In silico predictions for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.046% (130 heterozygotes). The variant has been previously described as a VUS and likely benign (ClinVar, Deafnessvariationdatabase, LOVD, Shearer, A. E., et al. (2014), Baux, D., et al. (2017)). An alternative change to histidine has also been reported as a VUS (Deafnessvariationdatabase). Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE with LOW CLINICAL RELEVANCE. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not specified Uncertain:1
The p.Asn886Ser variant in TECTA has been previously reported in 7 individuals with sensorineural hearing loss (Baux 2017, Hildebrand 2011, Sommen 2016, Baux 2017, LMM data). In 3 of these individuals a second TECTA variant was identified (p.Glu1950del, p.Val205Leu, p.Cys1372*), though only one was likely to be pathogenic (p.Cys1372*). Furthermore, one of the previously reported probands had a family history of autosomal dominant hearing loss, and while the variant segregated with the disease in 12 affected family members, a more likely pathogenic variant in TECTA (c.5383+5_5383+8delGTGA) was identified in cis with p.Asn886Ser, suggesting that p.Asn886Ser was less likely related to the hearing loss in this family (Hildebrand, 2011). This variant has been identified in 0.07% (98/128646) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Asn886Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to conflicting evidence, the clinical significance of the p.Asn886Ser variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, BS1_Supporting, BP2. -
Autosomal dominant nonsyndromic hearing loss 12;C1863655:Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1
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Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at