rs121908830

Variant names:

• chr2-96254050-G-A
• rs121908830
• NM_017849.4:c.475C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-96254050-G-A
• chr2-96254050-G-C

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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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 [Likely_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 rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.475C>T	p.Gln159*	stop_gained	Exon 4 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.475C>T	p.Gln159*	stop_gained	Exon 4 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.223C>T	p.Gln75*	stop_gained	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.223C>T	p.Gln75*	stop_gained	Exon 3 of 3		NP_001394212.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:2

Apr 26, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant is found in the last exon of TMEM127, therefore the resulting mRNA is predicted to escape nonsense-mediated decay. However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 22419703, 33051659, 28567294). Loss-of-function variation in TMEM127 is an established mechanism of disease (PMID: 20301715, 16266984). This variant has been previously reported as a heterozygous change in patients with pheochromocytoma (PMID: 20154675, 33051659). The c.475C>T (p.Gln159Ter) variant is absent from the gnomAD v4 population database and thus is presumed to be rare. Based on the available evidence, c.475C>T (p.Gln159Ter) is classified as Likely Pathogenic. -

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Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 20154675). ClinVar contains an entry for this variant (Variation ID: 108). 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. -

Pheochromocytoma, susceptibility to Other:1

Mar 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

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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;