2-96254031-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_017849.4(TMEM127):āc.494A>Gā(p.His165Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H165H) has been classified as Likely benign.
Frequency
Consequence
NM_017849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.494A>G | p.His165Arg | missense_variant | 4/4 | ENST00000258439.8 | |
TMEM127 | NM_001193304.3 | c.494A>G | p.His165Arg | missense_variant | 4/4 | ||
TMEM127 | NM_001407282.1 | c.242A>G | p.His81Arg | missense_variant | 3/3 | ||
TMEM127 | NM_001407283.1 | c.242A>G | p.His81Arg | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.494A>G | p.His165Arg | missense_variant | 4/4 | 1 | NM_017849.4 | P1 | |
TMEM127 | ENST00000432959.1 | c.494A>G | p.His165Arg | missense_variant | 4/4 | 1 | P1 | ||
TMEM127 | ENST00000435268.1 | c.242A>G | p.His81Arg | missense_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251486Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135916
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74308
ClinVar
Submissions by phenotype
Ovarian cancer Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The p.H165R variant (also known as c.494A>G), located in coding exon 3 of the TMEM127 gene, results from an A to G substitution at nucleotide position 494. The histidine at codon 165 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary pheochromocytoma-paraganglioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 165 of the TMEM127 protein (p.His165Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 241224). 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