NM_017849.4:c.292G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_017849.4(TMEM127):c.292G>A(p.Ala98Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000558 in 1,614,202 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. A98P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 5.72

Publications

5 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31807694).

BP6

Variant 2-96254950-C-T is Benign according to our data. Variant chr2-96254950-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241222.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000657 (10/152320) while in subpopulation AMR AF = 0.000392 (6/15310). AF 95% confidence interval is 0.00017. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4 link	c.292G>A	p.Ala98Thr	missense_variant	Exon 3 of 4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_001193304.3 link	c.292G>A	p.Ala98Thr	missense_variant	Exon 3 of 4		NP_001180233.1	O75204
TMEM127	NM_001407282.1 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 3		NP_001394211.1
TMEM127	NM_001407283.1 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 link	c.292G>A	p.Ala98Thr	missense_variant	Exon 3 of 4	1	NM_017849.4	ENSP00000258439.3		O75204

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000676

AC:

AN:

251384

AF XY:

0.0000662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1112010

Other (OTH)

AF:

0.000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000657

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.000392

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000225

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 28, 2024

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; Observed in an individual with head and neck paraganglioma (PMID: 33051659); This variant is associated with the following publications: (PMID: 21156949, 33051659) -

Sep 22, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000088 (10/113674 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 head and neck paraganglioma (PMID: 33051659 (2021)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary pheochromocytoma-paraganglioma

Uncertain:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 98 of the TMEM127 protein (p.Ala98Thr). This variant is present in population databases (rs369144563, gnomAD 0.009%). This missense change has been observed in individual(s) with head and neck paraganglioma (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 241222). 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 tolerated. 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. -

Sep 09, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TMEM127 c.292G>A (p.Ala98Thr) missense change has a maximum subpopulation frequency of 0.0088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-96920688-C-T). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in a 44-year-old female with a head and neck paraganglioma (PMID: 33051659). The tumor sample of this individual did not demonstrate loss of heterozygosity suggesting an uncertain role this variant in tumorigenesis. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Apr 03, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

May 30, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1

Jul 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM127 c.292G>A (p.Ala98Thr) results in a non-conservative amino acid change located in the Transmembrane protein 127, transmembrane region (IPR046795) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251384 control chromosomes (gnomAD). The observed variant frequency is approximately 216 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM127 causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (3.1e-07). c.292G>A has been reported in the literature in individuals affected with head and neck paraganglioma (Armaiz-Pena_2021). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 241222). Based on the evidence outlined above, the variant was classified as likely benign. -

Pheochromocytoma

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.030

T;T;.

Eigen

Benign

0.062

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.76

N;N;.

PhyloP100

5.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.62

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.88

P;P;.

Vest4

0.50

MVP

0.49

MPC

0.51

ClinPred

0.073

GERP RS

5.0

Varity_R

0.073

gMVP

0.86

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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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