rs1553436874
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000258439.8(TMEM127):c.532_533insT(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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y178Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TMEM127
ENST00000258439.8 frameshift
ENST00000258439.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.75
Genes affected
TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-96253992-T-TA is Pathogenic according to our data. Variant chr2-96253992-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.532_533insT | p.Tyr178LeufsTer48 | frameshift_variant | 4/4 | ENST00000258439.8 | NP_060319.1 | |
TMEM127 | NM_001193304.3 | c.532_533insT | p.Tyr178LeufsTer48 | frameshift_variant | 4/4 | NP_001180233.1 | ||
TMEM127 | NM_001407282.1 | c.280_281insT | p.Tyr94LeufsTer48 | frameshift_variant | 3/3 | NP_001394211.1 | ||
TMEM127 | NM_001407283.1 | c.280_281insT | p.Tyr94LeufsTer48 | frameshift_variant | 3/3 | NP_001394212.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.532_533insT | p.Tyr178LeufsTer48 | frameshift_variant | 4/4 | 1 | NM_017849.4 | ENSP00000258439 | P1 | |
TMEM127 | ENST00000432959.1 | c.532_533insT | p.Tyr178LeufsTer48 | frameshift_variant | 4/4 | 1 | ENSP00000416660 | P1 | ||
TMEM127 | ENST00000435268.1 | c.280_281insT | p.Tyr94LeufsTer48 | frameshift_variant | 3/3 | 3 | ENSP00000411810 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2023 | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 05, 2021 | 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. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 28855235; Invitae). ClinVar contains an entry for this variant (Variation ID: 421874). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TMEM127 function (PMID: 28855235). 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. 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. - |
Computational scores
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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