2-96254989-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017849.4(TMEM127):​c.253A>C​(p.Met85Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M85V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM127
NM_017849.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3810541).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TMEM127NM_017849.4 linkuse as main transcriptc.253A>C p.Met85Leu missense_variant 3/4 ENST00000258439.8
TMEM127NM_001407282.1 linkuse as main transcriptc.1A>C p.Met1? start_lost 2/3
TMEM127NM_001407283.1 linkuse as main transcriptc.1A>C p.Met1? start_lost 2/3
TMEM127NM_001193304.3 linkuse as main transcriptc.253A>C p.Met85Leu missense_variant 3/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TMEM127ENST00000258439.8 linkuse as main transcriptc.253A>C p.Met85Leu missense_variant 3/41 NM_017849.4 P1
TMEM127ENST00000432959.1 linkuse as main transcriptc.253A>C p.Met85Leu missense_variant 3/41 P1
TMEM127ENST00000435268.1 linkuse as main transcriptc.1A>C p.Met1? start_lost 2/33

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

Pheochromocytoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.018
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.011
T;T;.
Eigen
Benign
-0.19
Eigen_PC
Benign
0.061
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
.;T;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.26
T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
0.84
L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.24
N;N;N
REVEL
Benign
0.26
Sift
Benign
0.66
T;T;T
Sift4G
Benign
0.90
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.43
MutPred
0.28
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;
MVP
0.46
MPC
0.38
ClinPred
0.69
D
GERP RS
5.9
Varity_R
0.12
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771261665; hg19: chr2-96920727; API