chr2-96265379-C-T

Position:

chr2-96265379-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_017849.4(TMEM127):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000021 in 1,426,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.07

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 Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_017849.4 (TMEM127) was described as [Likely_pathogenic] in ClinVar as 126968

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-96265379-C-T is Pathogenic according to our data. Variant chr2-96265379-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 532514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM127	NM_017849.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4	ENST00000258439.8
TMEM127	NM_001193304.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4
TMEM127	NM_001407283.1 linkuse as main transcript	c.-9+490G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000157

AC:

AN:

1274416

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

624168

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:

0.00000194

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the TMEM127 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been reported in multiple individuals with pheochromocytomas (PCC) (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212). This mutation has also been identified in the homozygous state in a Turkish patient with bilateral PCC (Eijkelenkamp K et al. Clin GEnet. 2018 May;93(5):1049-1056). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2022

This sequence change affects the initiator methionine of the TMEM127 mRNA. The next in-frame methionine is located at codon 85. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID: 21156949). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 532514). Disruption of the initiator codon has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 29282712; Invitae). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.43

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-0.91

N;N

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0020

B;B

Vest4

0.94

MutPred

0.94

Loss of MoRF binding (P = 0.0982);Loss of MoRF binding (P = 0.0982);

MVP

0.80

ClinPred

0.99

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.73

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