2-96265165-C-G

Position:

chr2-96265165-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The ENST00000258439.8(TMEM127):c.217G>C(p.Gly73Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000863 in 1,611,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G73D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

TMEM127
ENST00000258439.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6B:1

Conservation

PhyloP100: 7.12

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]

TMEM127 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM127	NM_017849.4 linkuse as main transcript	c.217G>C	p.Gly73Arg	missense_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3 linkuse as main transcript	c.217G>C	p.Gly73Arg	missense_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1 linkuse as main transcript	c.-9+704G>C		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.217G>C	p.Gly73Arg	missense_variant	2/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.217G>C	p.Gly73Arg	missense_variant	2/4	1		ENSP00000416660	P1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000372

AC:

AN:

241688

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

131972

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000832

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000918

AC:

134

AN:

1459172

Hom.:

Cov.:

AF XY:

0.0000758

AC XY:

AN XY:

725764

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000578

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pheochromocytoma

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 07, 2024	The TMEM127 c.217G>C (p.Gly73Arg) missense change has a maximum subpopulation frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in an individual with pheochromocytoma (PMID: 22136840). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 12, 2023	- -
Likely pathogenic, no assertion criteria provided	literature only	Familial Cancer Clinic, Veneto Institute of Oncology	-	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2023	The frequency of this variant in the general population, 0.000081 (10/123534 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pheochromocytoma (PMID: 21156949 (2010)). A published functional study has reported that this variant does not have a deleterious effect on TMEM127 protein localization and expression (PMID: 32575117 (2020)), however additional studies are required to determine the global effect of this variant on TMEM127 protein function. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2024	Observed in an individual with pheochromocytoma (PMID: 21156949); Published functional studies demonstrate no damaging effect: cellular localization and protein expression levels similar to wildtype (PMID: 32575117); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 32575117, 33051659, 21156949, 22136840) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2023

The p.G73R variant (also known as c.217G>C), located in coding exon 1 of the TMEM127 gene, results from a G to C substitution at nucleotide position 217. The glycine at codon 73 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in an Italian male with an apparently sporadic adrenal paraganglioma diagnosed at age 44 (Yao L et al, JAMA 2010 Dec; 304(23):2611-9). 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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 09, 2023

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. Experimental studies have shown that this missense change does not substantially affect TMEM127 function (PMID: 32575117). 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: 126965). This missense change has been observed in individual(s) with pheochromocytoma (PMID: 21156949). This variant is present in population databases (rs121908820, gnomAD 0.008%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 73 of the TMEM127 protein (p.Gly73Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.10

T;T

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.79

MPC

1.2

ClinPred

0.37

GERP RS

4.6

Varity_R

0.36

gMVP

0.94

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over