2-96265330-G-A

Position:

chr2-96265330-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017849.4(TMEM127):c.52C>T(p.Pro18Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000526 in 1,520,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P18L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.22

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15515262).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM127	NM_017849.4 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	2/4	ENST00000258439.8
TMEM127	NM_001193304.3 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	2/4
TMEM127	NM_001407283.1 linkuse as main transcript	c.-9+539C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	2/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.52C>T	p.Pro18Ser	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000813

AC:

AN:

122928

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67710

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1368612

Hom.:

Cov.:

AF XY:

0.00000593

AC XY:

AN XY:

674070

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:

0.00

Gnomad4 NFE exome

AF:

0.00000467

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pheochromocytoma

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 11, 2023	The TMEM127 c.52C>T (p.Pro18Ser) missense change has a maximum subpopulation frequency of 0.018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/), however data at this position may not be reliable due to a mean depth of coverage less than 30X. The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with paraganglioma or pheochromocytoma. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The p.P18S variant (also known as c.52C>T), located in coding exon 1 of the TMEM127 gene, results from a C to T substitution at nucleotide position 52. The proline at codon 18 is replaced by serine, an amino acid with similar properties. This variant has been identified in at least one patient with a personal and family history of breast and/or ovarian cancer (Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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

Dec 08, 2023

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 18 of the TMEM127 protein (p.Pro18Ser). 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: 486533). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.032

T;T

Eigen

Benign

0.0059

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.24

Sift

Benign

0.27

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0070

B;B

Vest4

0.26

MutPred

0.24

Gain of phosphorylation at P18 (P = 0.0012);Gain of phosphorylation at P18 (P = 0.0012);

MVP

0.32

MPC

0.42

ClinPred

0.32

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.61

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