2-96253904-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_017849.4(TMEM127):c.621G>A(p.Ala207Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,613,928 control chromosomes in the GnomAD database, including 25,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A207A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1782 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23773 hom. )

Consequence

TMEM127
NM_017849.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -4.45

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-96253904-C-T is Benign according to our data. Variant chr2-96253904-C-T is described in ClinVar as Benign. ClinVar VariationId is 45824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4 link	c.621G>A	p.Ala207Ala	synonymous_variant	Exon 4 of 4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_001193304.3 link	c.621G>A	p.Ala207Ala	synonymous_variant	Exon 4 of 4		NP_001180233.1	O75204
TMEM127	NM_001407282.1 link	c.369G>A	p.Ala123Ala	synonymous_variant	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1 link	c.369G>A	p.Ala123Ala	synonymous_variant	Exon 3 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 link	c.621G>A	p.Ala207Ala	synonymous_variant	Exon 4 of 4	1	NM_017849.4	ENSP00000258439.3		O75204

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21620

AN:

151974

Hom.:

1777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0640

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.179

Gnomad EAS

AF:

0.0828

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.163

AC:

40976

AN:

251306

AF XY:

0.171

show subpopulations

Gnomad AFR exome

AF:

0.0601

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.175

Gnomad EAS exome

AF:

0.0758

Gnomad FIN exome

AF:

0.152

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.194

GnomAD4 exome

AF:

0.174

AC:

254700

AN:

1461836

Hom.:

23773

Cov.:

AF XY:

0.178

AC XY:

129721

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0650

AC:

2175

AN:

33480

American (AMR)

AF:

0.126

AC:

5635

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4673

AN:

26136

East Asian (EAS)

AF:

0.0827

AC:

3285

AN:

39698

South Asian (SAS)

AF:

0.276

AC:

23781

AN:

86258

European-Finnish (FIN)

AF:

0.150

AC:

8033

AN:

53412

Middle Eastern (MID)

AF:

0.255

AC:

1471

AN:

5768

European-Non Finnish (NFE)

AF:

0.175

AC:

194782

AN:

1111972

Other (OTH)

AF:

0.180

AC:

10865

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

14125

28250

42374

56499

70624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6856

13712

20568

27424

34280

<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:

0.142

AC:

21644

AN:

152092

Hom.:

1782

Cov.:

AF XY:

0.145

AC XY:

10765

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0642

AC:

2665

AN:

41512

American (AMR)

AF:

0.161

AC:

2453

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

622

AN:

3468

East Asian (EAS)

AF:

0.0824

AC:

426

AN:

5168

South Asian (SAS)

AF:

0.270

AC:

1297

AN:

4812

European-Finnish (FIN)

AF:

0.145

AC:

1535

AN:

10588

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12062

AN:

67946

Other (OTH)

AF:

0.183

AC:

386

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

937

1874

2812

3749

4686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.166

Hom.:

3376

Bravo

AF:

0.133

Asia WGS

AF:

0.173

AC:

601

AN:

3478

EpiCase

AF:

0.186

EpiControl

AF:

0.181

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 21, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala207Ala in exon 4 of TMEM127: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified identified in 11.5% o f chromosomes from a broad, though clinically and racially unspecified populatio n by the 1000 Genomes project (dbSNP rs3852673). Ala207Ala in exon 4 of TMEM127 (rs3852673; allele frequency = 11.5%) -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 26, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The TMEM127 c.621G>A (p.Ala207Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts polymorphism outcome for this variant. 5/5 Alamut algorithms predict no significant change to normal splicing. This variant was found in 19810/121224 control chromosomes (1938 homozygotes) at a frequency of 0.1634165, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic TMEM127 variant (0.0000001), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign. Taken together and based on the high allele frequency in the general population, this variant is classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pheochromocytoma

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 18, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.19

(source)

DANN

Benign

0.69

PhyloP100

-4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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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