rs185702148
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_138691.3(TMC1):c.1189G>A(p.Asp397Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,052 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TMC1
NM_138691.3 missense
NM_138691.3 missense
Scores
1
3
14
Clinical Significance
Conservation
PhyloP100: 4.75
Genes affected
TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a topological_domain Extracellular (size 53) in uniprot entity TMC1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_138691.3
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.106783986).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.1189G>A | p.Asp397Asn | missense_variant | 15/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.1192G>A | p.Asp398Asn | missense_variant | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.1189G>A | p.Asp397Asn | missense_variant | 15/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251422Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461752Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727176
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74488
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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 | Nov 12, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp397Asn variant in TMC1 has not been previously reported in individuals with hearing lo ss. This variant has been identified in 2/8654 East Asian chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1857021 48); however, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analyses of the amino acid change do not provide strong support for or against an impact to the protein. In summar y, the clinical significance of the p.Asp397Asn variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35761346) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;.
REVEL
Benign
Sift
Benign
T;.;.;T;.
Sift4G
Benign
T;.;.;T;.
Polyphen
B;B;.;B;.
Vest4
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