rs1553436874
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_017849.4(TMEM127):c.532dupT(p.Tyr178LeufsTer48) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_017849.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.532dupT | p.Tyr178LeufsTer48 | frameshift_variant | Exon 4 of 4 | ENST00000258439.8 | NP_060319.1 | |
TMEM127 | NM_001193304.3 | c.532dupT | p.Tyr178LeufsTer48 | frameshift_variant | Exon 4 of 4 | NP_001180233.1 | ||
TMEM127 | NM_001407282.1 | c.280dupT | p.Tyr94LeufsTer48 | frameshift_variant | Exon 3 of 3 | NP_001394211.1 | ||
TMEM127 | NM_001407283.1 | c.280dupT | p.Tyr94LeufsTer48 | frameshift_variant | Exon 3 of 3 | NP_001394212.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.532dupT | p.Tyr178LeufsTer48 | frameshift_variant | Exon 4 of 4 | 1 | NM_017849.4 | ENSP00000258439.3 | ||
TMEM127 | ENST00000432959.1 | c.532dupT | p.Tyr178LeufsTer48 | frameshift_variant | Exon 4 of 4 | 1 | ENSP00000416660.1 | |||
TMEM127 | ENST00000435268.1 | c.280dupT | p.Tyr94LeufsTer48 | frameshift_variant | Exon 3 of 3 | 3 | ENSP00000411810.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect: variant results in diffuse subcellular localization and significantly reduced protein expression (Deng et al., 2017; Deng et al., 2018; Flores et al., 2020); Frameshift variant predicted to result in protein truncation, as the last 61 amino acids are replaced with 47 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28384794, 28855235, 32575117, 21156949, 29547888) -
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
This sequence change creates a premature translational stop signal (p.Tyr178Leufs*48) in the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the TMEM127 protein. 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. This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Ala186Argfs*44) have been observed in individuals with TMEM127-related conditions (PMID: 28384794). This suggests that this may be a clinically significant region of the protein. Experimental studies have shown that this premature translational stop signal affects TMEM127 function (PMID: 28855235). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 421874). This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 28855235; Invitae). This variant is not present in population databases (gnomAD no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at