rs144343770
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS1
The NM_005422.4(TECTA):c.5836T>C(p.Tyr1946His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,614,182 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 Likely benign (★★★).
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00030 ( 1 hom. )
Consequence
TECTA
NM_005422.4 missense
NM_005422.4 missense
Scores
9
5
4
Clinical Significance
Conservation
PhyloP100: 7.64
Genes affected
TECTA (HGNC:11720): (tectorin alpha) The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major noncollagenous components of the tectorial membrane. Mutations in the TECTA gene have been shown to be responsible for autosomal dominant nonsyndromic hearing impairment and a recessive form of sensorineural pre-lingual non-syndromic deafness. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
PM1
?
In a domain ZP (size 254) in uniprot entity TECTA_HUMAN there are 28 pathogenic changes around while only 9 benign (76%) in NM_005422.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.031716913).
BP6
?
Variant 11-121168762-T-C is Benign according to our data. Variant chr11-121168762-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 165370.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-121168762-T-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000298 (436/1461880) while in subpopulation MID AF= 0.00243 (14/5768). AF 95% confidence interval is 0.00147. There are 1 homozygotes in gnomad4_exome. There are 228 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.5836T>C | p.Tyr1946His | missense_variant | 20/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.6778T>C | p.Tyr2260His | missense_variant | 26/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.5836T>C | p.Tyr1946His | missense_variant | 20/24 | 5 | NM_005422.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000348 AC: 53AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000493 AC: 124AN: 251460Hom.: 1 AF XY: 0.000456 AC XY: 62AN XY: 135904
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GnomAD4 exome AF: 0.000298 AC: 436AN: 1461880Hom.: 1 Cov.: 31 AF XY: 0.000314 AC XY: 228AN XY: 727240
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GnomAD4 genome ? AF: 0.000348 AC: 53AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74476
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:3Benign:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 05, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 16, 2017 | p.Tyr1946His in exon 19 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.6% (62/10152) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs144343770). - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | - - |
Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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. - |
Nonsyndromic genetic hearing loss Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jan 28, 2019 | The filtering allele frequency of the c.5836T>C (p.Tyr1946His) variant in the TECTA gene is 0.495% for Ashkenazi Jewish chromosomes by gnomAD (64/10370 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.8, which is above the threshold necessary to apply PP3. The HL EP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case since computational scores are error prone, especially when predicting pathogenicity. In summary, the HL EP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1, PP3. - |
TECTA-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;.;D
Sift4G
Pathogenic
D;.;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at