rs752254649
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_005422.4(TECTA):c.1123G>A(p.Val375Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,613,948 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
TECTA
NM_005422.4 missense
NM_005422.4 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 8.19
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=0.36477742).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TECTA | NM_005422.4 | c.1123G>A | p.Val375Ile | missense_variant | 7/24 | ENST00000392793.6 | |
TBCEL-TECTA | NM_001378761.1 | c.2080G>A | p.Val694Ile | missense_variant | 13/30 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECTA | ENST00000392793.6 | c.1123G>A | p.Val375Ile | missense_variant | 7/24 | 5 | NM_005422.4 | P4 | |
TECTA | ENST00000264037.2 | c.1123G>A | p.Val375Ile | missense_variant | 6/23 | 1 | P4 | ||
TECTA | ENST00000642222.1 | c.1123G>A | p.Val375Ile | missense_variant | 7/24 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251444Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135902
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GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461834Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 37AN XY: 727222
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74304
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
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 | Jan 09, 2018 | p.Val375Ile, c.1123G>A (TECTA; NM_005422.2; Chr11g.120989347G>A; GRCh37): The p. Val375Ile variant in TECTA has not been previously reported in individuals with hearing loss, but has been identified in 8/126686 of European chromosomes and 2/ 30782 of South Asian chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP 752254649). Although this variant has been seen in the general population, its frequency is not high enough to rule out a p athogenic role. Computational prediction tools and conservation analysis suggest that the p.Val375Ile variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical sign ificance of the p.Val375Ile variant is uncertain. ACMG/AMP Criteria applied: PM2 ; PP3 - |
Hearing impairment Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PM2_Moderate, PP2_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
D;.;D
Vest4
MutPred
Loss of ubiquitination at K379 (P = 0.0863);Loss of ubiquitination at K379 (P = 0.0863);Loss of ubiquitination at K379 (P = 0.0863);
MVP
MPC
ClinPred
T
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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