NM_005422.4:c.1085G>T
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_005422.4(TECTA):c.1085G>T(p.Ser362Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S362C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005422.4 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005422.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TECTA | NM_005422.4 | MANE Select | c.1085G>T | p.Ser362Ile | missense | Exon 7 of 24 | NP_005413.2 | ||
| TBCEL-TECTA | NM_001378761.1 | c.2042G>T | p.Ser681Ile | missense | Exon 13 of 30 | NP_001365690.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TECTA | ENST00000392793.6 | TSL:5 MANE Select | c.1085G>T | p.Ser362Ile | missense | Exon 7 of 24 | ENSP00000376543.1 | ||
| TECTA | ENST00000264037.2 | TSL:1 | c.1085G>T | p.Ser362Ile | missense | Exon 6 of 23 | ENSP00000264037.2 | ||
| TECTA | ENST00000642222.1 | c.1085G>T | p.Ser362Ile | missense | Exon 7 of 24 | ENSP00000493855.1 |
Frequencies
GnomAD3 genomes 0.000920 AC: 140AN: 152148Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000187 AC: 47AN: 251466 AF XY: 0.000125 show subpopulations
GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727242 show subpopulations
Age Distribution
GnomAD4 genome 0.000913 AC: 139AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74450 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31554319, 9590290, 21520338)
Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1Benign:1
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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness. Recessive variants that cause a premature termination codon result in a loss of function, whereas some dominant missense variants have also been suggested to act in a dominant negative mechanism. (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant deafness is usually caused by missense variants, whereas recessive deafness is generally a result of premature termination codon variants, however exceptions do exist (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (146 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated VWFD 1 domain (NCBI, PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to cysteine at the same residue has previously been reported in a patient with autosomal dominant non-syndromic hearing loss (PMID: 21520338, Deafness Variation Database). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported as likely benign in association with dominant deafness, however it has also been classified as a VUS in relation to recessive deafness (ClinVar, Deafness Variation Database). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Ser362Ile var iant in TECTA has not been previously reported in individuals with hearing loss but has been identified in 0.318% (14/4406) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14 3827620). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, while the clinical significance of the Ser362Ile variant is uncertain, its frequency sugge sts that it is more likely to be benign.
Inborn genetic diseases Uncertain:1
The c.1085G>T (p.S362I) alteration is located in exon 6 (coding exon 6) of the TECTA gene. This alteration results from a G to T substitution at nucleotide position 1085, causing the serine (S) at amino acid position 362 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1
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.
TECTA-related disorder Benign:1
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