rs1553437740
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_017849.4(TMEM127):c.100G>A(p.Ala34Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A34G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
TMEM127
NM_017849.4 missense
NM_017849.4 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 7.00
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM127 | NM_017849.4 | c.100G>A | p.Ala34Thr | missense_variant | 2/4 | ENST00000258439.8 | |
TMEM127 | NM_001193304.3 | c.100G>A | p.Ala34Thr | missense_variant | 2/4 | ||
TMEM127 | NM_001407283.1 | c.-9+587G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM127 | ENST00000258439.8 | c.100G>A | p.Ala34Thr | missense_variant | 2/4 | 1 | NM_017849.4 | P1 | |
TMEM127 | ENST00000432959.1 | c.100G>A | p.Ala34Thr | missense_variant | 2/4 | 1 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The p.A34T variant (also known as c.100G>A), located in coding exon 1 of the TMEM127 gene, results from a G to A substitution at nucleotide position 100. The alanine at codon 34 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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 | May 18, 2021 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a TMEM127-related disease. This sequence change replaces alanine with threonine at codon 34 of the TMEM127 protein (p.Ala34Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at A34 (P = 0.0197);Gain of glycosylation at A34 (P = 0.0197);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at