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
11
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]
TBCEL-TECTA (HGNC:54857): (TBCEL-TECTA readthrough) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | ENST00000392793.6 | NP_005413.2 | |
TBCEL-TECTA | NM_001378761.1 | c.2578G>A | p.Val860Met | missense_variant | 14/30 | NP_001365690.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | 5 | NM_005422.4 | ENSP00000376543.1 | ||
TECTA | ENST00000264037.2 | c.1621G>A | p.Val541Met | missense_variant | 7/23 | 1 | ENSP00000264037.2 | |||
TECTA | ENST00000642222.1 | c.1621G>A | p.Val541Met | missense_variant | 8/24 | ENSP00000493855.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
9
AN:
152222
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251248Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135768
GnomAD3 exomes
AF:
AC:
22
AN:
251248
Hom.:
AF XY:
AC XY:
14
AN XY:
135768
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000671 AC: 98AN: 1460956Hom.: 0 Cov.: 35 AF XY: 0.0000826 AC XY: 60AN XY: 726582
GnomAD4 exome
AF:
AC:
98
AN:
1460956
Hom.:
Cov.:
35
AF XY:
AC XY:
60
AN XY:
726582
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74370
GnomAD4 genome
AF:
AC:
9
AN:
152222
Hom.:
Cov.:
33
AF XY:
AC XY:
7
AN XY:
74370
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
10
Asia WGS
AF:
AC:
2
AN:
3478
EpiCase
AF:
EpiControl
AF:
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 | 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. - |
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. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Located in the zonadhesin domain (PMID: 31554319, 9590290, 21520338); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31554319, 9590290, 21520338) - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 06, 2023 | - - |
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
LIST_S2
Benign
.;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M
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
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