rs200821009
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_005422.4(TECTA):c.2967C>A(p.His989Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,978 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
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000050 ( 1 hom. )
Consequence
TECTA
NM_005422.4 missense
NM_005422.4 missense
Scores
5
7
6
Clinical Significance
Conservation
PhyloP100: -0.0640
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 -7 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.072065145).
BP6
?
Variant 11-121137446-C-A is Benign according to our data. Variant chr11-121137446-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505413.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000986 (15/152092) while in subpopulation EAS AF= 0.00295 (15/5084). AF 95% confidence interval is 0.00182. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.2967C>A | p.His989Gln | missense_variant | 11/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.3924C>A | p.His1308Gln | missense_variant | 17/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.2967C>A | p.His989Gln | missense_variant | 11/24 | 5 | NM_005422.4 | P4 | |
TECTA | ENST00000264037.2 | c.2967C>A | p.His989Gln | missense_variant | 10/23 | 1 | P4 | ||
TECTA | ENST00000642222.1 | c.2967C>A | p.His989Gln | missense_variant | 11/24 | A1 | |||
TECTA | ENST00000645008.1 | c.276C>A | p.His92Gln | missense_variant | 2/15 |
Frequencies
GnomAD3 genomes ? AF: 0.0000987 AC: 15AN: 151974Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000151 AC: 38AN: 251114Hom.: 1 AF XY: 0.000169 AC XY: 23AN XY: 135694
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GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461886Hom.: 1 Cov.: 32 AF XY: 0.0000550 AC XY: 40AN XY: 727246
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GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2023 | Identified in patients with sensorineural hearing loss in published literature, however the hearing loss may have been due to a variant in a different gene in all cases (Ishikawa et al., 2014; Santos-Cortez et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24655070, 33924653, 21520338, 31554319, 9590290) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 06, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.His989Gln var iant in TECTA has been reported in 1 Japanese family with hearing loss; however, the hearing loss was likely due to a variant in a different gene (Ishikawa 2014 ). This variant has been identified in 0.2% of East Asian chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200821 009). Computational prediction tools and conservation analysis suggest that the p.His989Gln variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, while the clinical signific ance of the p.His989Gln variant is uncertain, these data suggest that it is more likely to be benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
D;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;D
Sift4G
Pathogenic
D;.;D
Polyphen
D;.;D
Vest4
MutPred
Gain of disorder (P = 0.0973);Gain of disorder (P = 0.0973);Gain of disorder (P = 0.0973);
MVP
MPC
ClinPred
T
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