rs28941781
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_147196.3(TMIE):c.274C>T(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,800 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).
Frequency
Consequence
NM_147196.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMIE | NM_147196.3 | c.274C>T | p.Arg92Trp | missense_variant | Exon 3 of 4 | ENST00000643606.3 | NP_671729.2 | |
TMIE | NM_001370524.1 | c.115C>T | p.Arg39Trp | missense_variant | Exon 3 of 4 | NP_001357453.1 | ||
TMIE | NM_001370525.1 | c.115C>T | p.Arg39Trp | missense_variant | Exon 4 of 5 | NP_001357454.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMIE | ENST00000643606.3 | c.274C>T | p.Arg92Trp | missense_variant | Exon 3 of 4 | NM_147196.3 | ENSP00000494576.2 | |||
TMIE | ENST00000644830.1 | c.115C>T | p.Arg39Trp | missense_variant | Exon 3 of 4 | ENSP00000495111.1 | ||||
TMIE | ENST00000651652.1 | c.172C>T | p.Arg58Trp | missense_variant | Exon 2 of 2 | ENSP00000498953.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249468Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135370
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461800Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20AN XY: 727202
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 6 Pathogenic:2Uncertain:1
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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The TMIE c.274C>T (p.Arg92Trp) missense variant has been reported in a homozygous state in three siblings from one consanguineous family with autosomal recessive nonsyndromic hearing loss (Naz et al. 2002). The variant was absent from two unaffected siblings. No other genes were screened in this study. The p.Arg92Trp variant was absent from 254 controls but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg92Trp variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for the recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at