rs397517841
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_138691.3(TMC1):c.403G>A(p.Gly135Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G135G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
TMC1
NM_138691.3 missense
NM_138691.3 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 6.64
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.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.403G>A | p.Gly135Arg | missense_variant | 9/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.406G>A | p.Gly136Arg | missense_variant | 6/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.403G>A | p.Gly135Arg | missense_variant | 9/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251388Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD3 exomes
AF:
AC:
1
AN:
251388
Hom.:
AF XY:
AC XY:
1
AN XY:
135858
Gnomad AFR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad SAS exome
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Gnomad FIN exome
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GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
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 | Feb 01, 2011 | Variant classified as Uncertain Significance - Favor Benign. The Gly135Arg varia nt in TMC1 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across mammals and birds and computati onal analyses (PolyPhen2, SIFT) suggest that the Gly135Arg variant may impact th e protein. However, this information is not predictive enough to assume pathogen icity. In summary, the clinical significance of this variant cannot be determine d with certainty at this time. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;.;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;M
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D
Sift4G
Uncertain
D;.;.;D
Polyphen
D;D;.;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);.;Gain of MoRF binding (P = 0.0199);
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