rs370652301
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_005422.4(TECTA):c.1621G>A(p.Val541Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,178 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).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000067 ( 0 hom. )
Consequence
TECTA
NM_005422.4 missense
NM_005422.4 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 2.45
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 Likely_benign. Variant got -1 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29842472).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.2578G>A | p.Val860Met | missense_variant | 14/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | 5 | NM_005422.4 | P4 | |
TECTA | ENST00000264037.2 | c.1621G>A | p.Val541Met | missense_variant | 7/23 | 1 | P4 | ||
TECTA | ENST00000642222.1 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251248Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135768
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GnomAD4 exome AF: 0.0000671 AC: 98AN: 1460956Hom.: 0 Cov.: 35 AF XY: 0.0000826 AC XY: 60AN XY: 726582
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74370
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 12 Pathogenic:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Feb 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Jun 09, 2024 | A very rare variant predicted deleterious by most prediction programs. The variant is located in the TECTA ZA domain. Known AD mutations in this domain are known to be involved in high-tone HL (PMID: 31554319), the same type of HL as of this proband - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 03, 2015 | The p.Val541Met variant in TECTA has not been previously reported in individuals with hearing loss, but has been identified in 7/16504 South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs370652301). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analyses do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Val5 41Met variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 18, 2019 | The TECTA c.1621G>A; p.Val541Met variant (rs370652301), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 229291). This variant is found in the general population with an overall allele frequency of 0.008% (24/282,660 alleles) in the Genome Aggregation Database. The valine at codon 541 is moderately conserved (Alamut v.2.11) and computational analyses (SIFT: tolerated, PolyPhen-2; probably damaging) predict conflicting effects of this variant on protein structure/function. Thus, based on the available information, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Located in the zonadhesin domain (Yasukawa et al., 2019; Verhoeven et al., 1998; Hildebrand et al., 2011); This variant is associated with the following publications: (PMID: 31554319, 9590290, 21520338) - |
Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 06, 2021 | PM2, PP2, PP3 - |
TECTA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 20, 2023 | The TECTA c.1621G>A variant is predicted to result in the amino acid substitution p.Val541Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-120996428-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Benign
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at