rs397517834
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_138691.3(TMC1):c.1070A>G(p.Asn357Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N357N) has been classified as Likely benign.
Frequency
Consequence
NM_138691.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.1070A>G | p.Asn357Ser | missense_variant | 15/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.1073A>G | p.Asn358Ser | missense_variant | 12/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.1070A>G | p.Asn357Ser | missense_variant | 15/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251028Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135656
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461050Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726830
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2023 | The c.1070A>G (p.N357S) alteration is located in exon 15 (coding exon 11) of the TMC1 gene. This alteration results from a A to G substitution at nucleotide position 1070, causing the asparagine (N) at amino acid position 357 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 02, 2010 | Asn357Ser in exon 15 of TMC1: This variant has not been reported in the literatu re but was identified by our laboratory in an Usher patient with a clear alterna te etiology for disease. This residue is conserved in mammals but not in other s pecies and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a h igh likelihood of impact to the protein. In summary, this variant is most likel y benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at