rs121908822

Variant names:

• chr2-96254973-ACTGT-A
• rs121908822
• NM_017849.4:c.265_268delACAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017849.4(TMEM127):​c.265_268delACAG​(p.Thr89CysfsTer34) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T89T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.32
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96254973-ACTGT-A is Pathogenic according to our data. Variant chr2-96254973-ACTGT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.265_268delACAG	p.Thr89CysfsTer34	frameshift_variant	Exon 3 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.265_268delACAG	p.Thr89CysfsTer34	frameshift_variant	Exon 3 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.13_16delACAG	p.Thr5CysfsTer34	frameshift_variant	Exon 2 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.13_16delACAG	p.Thr5CysfsTer34	frameshift_variant	Exon 2 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.265_268delACAG	p.Thr89CysfsTer34	frameshift_variant	Exon 3 of 4	1	NM_017849.4	ENSP00000258439.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:2

Apr 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 150 amino acids are replaced with 33 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21156949, 20154675) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 28, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265_268delACAG pathogenic mutation, located in coding exon 2 of the TMEM127 gene, results from a deletion of 4 nucleotides at nucleotide positions 265 to 268, causing a translational frameshift with a predicted alternate stop codon (p.T89Cfs*34). This alteration occurs near the 3' terminus of the TMEM127 gene and is not expected to trigger nonsense-mediated mRNA decay; however, this impacts the last 117 amino acids of the protein. Premature stop codons are typically deleterious in nature and this variant has been reported in an individual diagnosed with bilateral pheochromocytomas at age 46 (Yao L et al. JAMA. 2010 Dec;304:2611-9). This variant has also been seen in individuals with early onset pheochromocytomas and/or features consistent with TMEM127-related hereditary pheochromocytoma-paraganglioma (Internal Ambry data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Feb 27, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with bilateral pheochromocytoma (PMID: 20154675). This variant is also known as c.264_267delCAGA in the literature. ClinVar contains an entry for this variant (Variation ID: 126966). A different truncation (p.Gln157*) that lies downstream of this variant has been determined to be pathogenic (PMID: 22419703, Invitae). This suggests that deletion of this region of the TMEM127 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the TMEM127 gene (p.Thr89Cysfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 150 amino acids of the TMEM127 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121908822; hg19: chr2-96920711;