rs1553437028
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017849.4(TMEM127):c.283del(p.Val95SerfsTer29) 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
TMEM127
NM_017849.4 frameshift
NM_017849.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.46
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 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-96254958-AC-A is Pathogenic according to our data. Variant chr2-96254958-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 463843.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.283del | p.Val95SerfsTer29 | frameshift_variant | 3/4 | ENST00000258439.8 | |
TMEM127 | NM_001193304.3 | c.283del | p.Val95SerfsTer29 | frameshift_variant | 3/4 | ||
TMEM127 | NM_001407282.1 | c.31del | p.Val11SerfsTer29 | frameshift_variant | 2/3 | ||
TMEM127 | NM_001407283.1 | c.31del | p.Val11SerfsTer29 | frameshift_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.283del | p.Val95SerfsTer29 | frameshift_variant | 3/4 | 1 | NM_017849.4 | P1 | |
TMEM127 | ENST00000432959.1 | c.283del | p.Val95SerfsTer29 | frameshift_variant | 3/4 | 1 | P1 | ||
TMEM127 | ENST00000435268.1 | c.31del | p.Val11SerfsTer29 | frameshift_variant | 2/3 | 3 |
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
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2017 | For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (p.Gln157*) has been reported in individuals affected with pheochromocytoma and determined to be pathogenic (PMID: 22419703, Invitae). This suggests that deletion of this region of the TMEM127 protein is causative of disease. This variant has not been reported in the literature in individuals with TMEM127-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TMEM127 gene (p.Val95Serfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acids of the TMEM127 protein. - |
Computational scores
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Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at