NM_017849.4:c.253A>G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_017849.4(TMEM127):c.253A>G(p.Met85Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_017849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.253A>G | p.Met85Val | missense_variant | Exon 3 of 4 | ENST00000258439.8 | NP_060319.1 | |
TMEM127 | NM_001407282.1 | c.1A>G | p.Met1? | start_lost | Exon 2 of 3 | NP_001394211.1 | ||
TMEM127 | NM_001407283.1 | c.1A>G | p.Met1? | start_lost | Exon 2 of 3 | NP_001394212.1 | ||
TMEM127 | NM_001193304.3 | c.253A>G | p.Met85Val | missense_variant | Exon 3 of 4 | NP_001180233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.253A>G | p.Met85Val | missense_variant | Exon 3 of 4 | 1 | NM_017849.4 | ENSP00000258439.3 | ||
TMEM127 | ENST00000432959.1 | c.253A>G | p.Met85Val | missense_variant | Exon 3 of 4 | 1 | ENSP00000416660.1 | |||
TMEM127 | ENST00000435268.1 | c.1A>G | p.Met1? | start_lost | Exon 2 of 3 | 3 | ENSP00000411810.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251290Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135840
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727232
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
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The TMEM127 c.253A>G (p.Met85Val) variant has been reported in the published literature in in individuals with mesothelioma and thyroid cancer (PMID: 29625052 (2018), 36451132 (2022)). The frequency of this variant in the general population, 0.000054 (7/129020 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1
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Pheochromocytoma Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.M85V variant (also known as c.253A>G), located in coding exon 2 of the TMEM127 gene, results from an A to G substitution at nucleotide position 253. The methionine at codon 85 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Hereditary pheochromocytoma-paraganglioma Uncertain:1
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 85 of the TMEM127 protein (p.Met85Val). This variant is present in population databases (rs771261665, gnomAD 0.006%). This missense change has been observed in individual(s) with mesothelioma (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 186566). 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 tolerated. 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