rs121908818
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_017849.4(TMEM127):c.158G>C(p.Trp53Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,603,718 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W53C) has been classified as Uncertain significance.
Frequency
Consequence
NM_017849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.158G>C | p.Trp53Ser | missense_variant | 2/4 | ENST00000258439.8 | |
TMEM127 | NM_001193304.3 | c.158G>C | p.Trp53Ser | missense_variant | 2/4 | ||
TMEM127 | NM_001407283.1 | c.-9+645G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.158G>C | p.Trp53Ser | missense_variant | 2/4 | 1 | NM_017849.4 | P1 | |
TMEM127 | ENST00000432959.1 | c.158G>C | p.Trp53Ser | missense_variant | 2/4 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451464Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 721704
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74384
ClinVar
Submissions by phenotype
Pheochromocytoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Familial Cancer Clinic, Veneto Institute of Oncology | - | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 18, 2022 | The c.158G>C (p.W53S) alteration is located in exon 2 (coding exon 1) of the TMEM127 gene. This alteration results from a G to C substitution at nucleotide position 158, causing the tryptophan (W) at amino acid position 53 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary pheochromocytoma-paraganglioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 126963). This missense change has been observed in individual(s) with pheochromocytomas and/or paragangliomas (PMID: 21156949, 22136840). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 53 of the TMEM127 protein (p.Trp53Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at