rs370088722
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_138691.3(TMC1):c.674C>T(p.Pro225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
TMC1
NM_138691.3 missense
NM_138691.3 missense
Scores
8
5
5
Clinical Significance
Conservation
PhyloP100: 6.95
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 Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 9-72754817-C-T is Pathogenic according to our data. Variant chr9-72754817-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72754817-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.674C>T | p.Pro225Leu | missense_variant | 12/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.677C>T | p.Pro226Leu | missense_variant | 9/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.674C>T | p.Pro225Leu | missense_variant | 12/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251340Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135838
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727196
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152154Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74330
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the TMC1 protein (p.Pro225Leu). This variant is present in population databases (rs370088722, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 33111345, 34523024). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 47876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMC1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2015 | The p.Pro225Leu variant in TMC1 has been identified by our laboratory in 1 indiv idual with hearing loss in the compound heterozygous state with a second pathoge nic variant. This variant has also been identified in 2/66630 European American chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs370088722). Although this variant has been seen in the general po pulation, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provi de strong support for or against an impact to the protein. However, the presenc e of this variant in combination with a reported pathogenic variant and in an in dividual with clinical features of hearing loss increases the likelihood that th e Pro225Leu variant is pathogenic. In summary, although additional studies are r equired to fully establish its clinical significance, this variant is likely pat hogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Uncertain
Sift
Benign
T;.;.;T;.
Sift4G
Benign
T;.;.;T;.
Polyphen
D;D;.;D;.
Vest4
MVP
MPC
ClinPred
D
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