chr11-121125797-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS1_Supporting
The NM_005422.4(TECTA):c.1699G>A(p.Ala567Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 1 hom. )
Consequence
TECTA
NM_005422.4 missense
NM_005422.4 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 6.62
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 Uncertain_significance. Variant got 0 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.808
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000164 (24/1461684) 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 12 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.1699G>A | p.Ala567Thr | missense_variant | 8/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.2656G>A | p.Ala886Thr | missense_variant | 14/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.1699G>A | p.Ala567Thr | missense_variant | 8/24 | 5 | NM_005422.4 | P4 | |
TECTA | ENST00000264037.2 | c.1699G>A | p.Ala567Thr | missense_variant | 7/23 | 1 | P4 | ||
TECTA | ENST00000642222.1 | c.1699G>A | p.Ala567Thr | missense_variant | 8/24 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461684Hom.: 1 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727150
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 03, 2017 | The p.Ala567Thr variant in TECTA has been reported in one individual with hearin g loss by our laboratory; however, an alternate explanation for their hearing lo ss was identified. This variant was absent from large population studies. Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala567Thr variant is uncertain. - |
Autosomal dominant nonsyndromic hearing loss 12;C1863655:Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 15, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2023 | Not observed at a significant frequency in large population cohorts (gnomAD); however, it has been identified at GeneDx in multiple individuals reported to be of Qatari background, including one homozygous occurrence, undergoing testing for a variety of indications; 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; This variant is associated with the following publications: (PMID: 9590290, 21520338, 31554319) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
N;.;N
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Uncertain
D;.;D
Polyphen
P;.;P
Vest4
MutPred
Loss of loop (P = 0.3664);Loss of loop (P = 0.3664);Loss of loop (P = 0.3664);
MVP
MPC
ClinPred
D
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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