NM_017849.4:c.292G>C
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3
The NM_017849.4(TMEM127):c.292G>C(p.Ala98Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,084 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. A98T) has been classified as Likely benign.
Frequency
Consequence
NM_017849.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- pheochromocytomaInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- renal cell carcinomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.292G>C | p.Ala98Pro | missense_variant | Exon 3 of 4 | ENST00000258439.8 | NP_060319.1 | |
TMEM127 | NM_001193304.3 | c.292G>C | p.Ala98Pro | missense_variant | Exon 3 of 4 | NP_001180233.1 | ||
TMEM127 | NM_001407282.1 | c.40G>C | p.Ala14Pro | missense_variant | Exon 2 of 3 | NP_001394211.1 | ||
TMEM127 | NM_001407283.1 | c.40G>C | p.Ala14Pro | missense_variant | Exon 2 of 3 | NP_001394212.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251384 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727242 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
The p.A98P variant (also known as c.292G>C), located in coding exon 2 of the TMEM127 gene, results from a G to C substitution at nucleotide position 292. The alanine at codon 98 is replaced by proline, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary pheochromocytoma-paraganglioma Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 98 of the TMEM127 protein (p.Ala98Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 845318). 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. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at