2-96254848-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_017849.4(TMEM127):​c.394G>T​(p.Ala132Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM127
NM_017849.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a chain Transmembrane protein 127 (size 237) in uniprot entity TM127_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_017849.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM127NM_017849.4 linkuse as main transcriptc.394G>T p.Ala132Ser missense_variant 3/4 ENST00000258439.8 NP_060319.1
TMEM127NM_001193304.3 linkuse as main transcriptc.394G>T p.Ala132Ser missense_variant 3/4 NP_001180233.1
TMEM127NM_001407282.1 linkuse as main transcriptc.142G>T p.Ala48Ser missense_variant 2/3 NP_001394211.1
TMEM127NM_001407283.1 linkuse as main transcriptc.142G>T p.Ala48Ser missense_variant 2/3 NP_001394212.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM127ENST00000258439.8 linkuse as main transcriptc.394G>T p.Ala132Ser missense_variant 3/41 NM_017849.4 ENSP00000258439 P1
TMEM127ENST00000432959.1 linkuse as main transcriptc.394G>T p.Ala132Ser missense_variant 3/41 ENSP00000416660 P1
TMEM127ENST00000435268.1 linkuse as main transcriptc.142G>T p.Ala48Ser missense_variant 2/33 ENSP00000411810

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 22, 2023This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. 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: 2130969). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 132 of the TMEM127 protein (p.Ala132Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Uncertain
0.077
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.029
T;T;.
Eigen
Benign
0.047
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Benign
0.072
D
MetaRNN
Uncertain
0.58
D;D;D
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
1.4
L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.86
N;N;N
REVEL
Uncertain
0.38
Sift
Benign
0.30
T;T;T
Sift4G
Benign
0.10
T;T;T
Polyphen
0.30
B;B;.
Vest4
0.75
MutPred
0.36
Gain of MoRF binding (P = 0.2532);Gain of MoRF binding (P = 0.2532);.;
MVP
0.53
MPC
0.94
ClinPred
0.87
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.15
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96920586; API