rs121908830

Positions:

• chr2-96254050-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017849.4(TMEM127):​c.475C>T​(p.Gln159*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.39

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.338 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96254050-G-A is Pathogenic according to our data. Variant chr2-96254050-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-96254050-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.475C>T	p.Gln159*	stop_gained	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.475C>T	p.Gln159*	stop_gained	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.223C>T	p.Gln75*	stop_gained	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.223C>T	p.Gln75*	stop_gained	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.475C>T	p.Gln159*	stop_gained	4/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.475C>T	p.Gln159*	stop_gained	4/4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.223C>T	p.Gln75*	stop_gained	3/3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Familial Cancer Clinic, Veneto Institute of Oncology

-

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2024

The p.Q159* pathogenic mutation (also known as c.475C>T), located in coding exon 3 of the TMEM127 gene, results from a C to T substitution at nucleotide position 475. This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 80 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in a family with multiple family members diagnosed with bilateral pheochromocytomas from 48y to 72y (Qin Y et al. Nat Genet. 2010 Mar; 42(3):229-33). 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

Oct 06, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Tyr178Leufs*48) have been determined to be pathogenic (PMID: 28855235, 28384794). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 20154675). ClinVar contains an entry for this variant (Variation ID: 108). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TMEM127 gene (p.Gln159*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acids of the TMEM127 protein. -

Pheochromocytoma, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.83
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs121908830; hg19: chr2-96919788;