rs727503483
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_138691.3(TMC1):c.1532C>A(p.Pro511His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P511L) has been classified as Pathogenic.
Frequency
Consequence
NM_138691.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.1532C>A | p.Pro511His | missense_variant | 17/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.1535C>A | p.Pro512His | missense_variant | 14/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.1532C>A | p.Pro511His | missense_variant | 17/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461854Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | TMC1 c.1532C>A, p.P511H alters a highly conserved residue in TMC1. The variant is compound heterozygous with TMC1 c.100C>T, p.R34* in 2 Palestinian children, one with moderate HL and the other with profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 23, 2019 | The p.Pro511His variant has been reported in 1 Libyan individual by our laboratory. The variant was identified in the homozygous state, segregated in an affected sibling, and was confirmed heterozygous in the unaffected parents. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2, PP1, PP3, PM3_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at