rs555517698
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7
The NM_138691.3(TMC1):c.2178G>A(p.Ala726=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,546 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
TMC1
NM_138691.3 synonymous
NM_138691.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.434
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 Benign. Variant got -9 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
?
Variant 9-72830499-G-A is Benign according to our data. Variant chr9-72830499-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 505348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-0.434 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.2178G>A | p.Ala726= | synonymous_variant | 22/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.2181G>A | p.Ala727= | synonymous_variant | 19/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.2178G>A | p.Ala726= | synonymous_variant | 22/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152026Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250938Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135816
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461402Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727006
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74380
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 13, 2016 | p.Ala726Ala in exon 22 of TMC1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1/66350 European c hromosomes and in 1/16482 South Asian chromosomes by the Exome Aggregation Conso rtium (ExAC, http://exac.broadinstitute.org; dbSNP rs555517698). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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