2-96265246-T-C

Position:

chr2-96265246-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_017849.4(TMEM127):c.136A>G(p.Thr46Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000313 in 1,595,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 5.41

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 Benign. Variant got -7 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

BP4

Computational evidence support a benign effect (MetaRNN=0.040671766).

BP6

Variant 2-96265246-T-C is Benign according to our data. Variant chr2-96265246-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463838.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM127	NM_017849.4 linkuse as main transcript	c.136A>G	p.Thr46Ala	missense_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3 linkuse as main transcript	c.136A>G	p.Thr46Ala	missense_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1 linkuse as main transcript	c.-9+623A>G		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.136A>G	p.Thr46Ala	missense_variant	2/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.136A>G	p.Thr46Ala	missense_variant	2/4	1		ENSP00000416660	P1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000470

AC:

AN:

212656

Hom.:

AF XY:

0.0000256

AC XY:

AN XY:

117228

show subpopulations

Gnomad AFR exome

AF:

0.000723

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:

0.000184

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1443154

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

717190

show subpopulations

Gnomad4 AFR exome

AF:

0.000602

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000184

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000673

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000687

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000666

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	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 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2022	- -

TMEM127-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2022

The TMEM127 c.136A>G variant is predicted to result in the amino acid substitution p.Thr46Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.085% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-96930984-T-C) and has conflicting interpretations of likely benign and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/463838/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Pheochromocytoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The p.T46A variant (also known as c.136A>G), located in coding exon 1 of the TMEM127 gene, results from an A to G substitution at nucleotide position 136. The threonine at codon 46 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.018

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.80

.;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.57

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.020

B;B

Vest4

0.52

MVP

0.69

MPC

0.41

ClinPred

0.060

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.34

gMVP

0.86

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