2-96265246-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T46S) has been classified as Uncertain significance.

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:5B:2

Conservation

PhyloP100: 5.41

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TMEM127 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 46 uncertain 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 VariationId is 463838.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000184 (28/152316) while in subpopulation AFR AF = 0.000673 (28/41590). AF 95% confidence interval is 0.000478. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMEM127	NM_017849.4 link	c.136A>G	p.Thr46Ala	missense_variant	Exon 2 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3 link	c.136A>G	p.Thr46Ala	missense_variant	Exon 2 of 4		NP_001180233.1
TMEM127	NM_001407283.1 link	c.-9+623A>G		intron_variant	Intron 1 of 2		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 link	c.136A>G	p.Thr46Ala	missense_variant	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3

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

GnomAD2 exomes

AF:

0.0000470

AC:

AN:

212656

AF XY:

0.0000256

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 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

African (AFR)

AF:

0.000602

AC:

AN:

33248

American (AMR)

AF:

0.00

AC:

AN:

43108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25810

East Asian (EAS)

AF:

0.00

AC:

AN:

39102

South Asian (SAS)

AF:

0.00

AC:

AN:

84234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106882

Other (OTH)

AF:

0.0000167

AC:

AN:

59782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000673

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000357

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:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

May 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 10, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMEM127-related disorder

Uncertain:1

Nov 04, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 21, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1

Jun 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.018

Eigen_PC

Benign

0.21

LIST_S2

Benign

0.0

.;T

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.5

L;L

PhyloP100

5.4

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-2.0

N;N

Sift

Benign

0.57

T;T

Sift4G

Benign

0.47

T;T

Vest4

0.52

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

Mutation Taster

=36/64

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over