2-96254973-ACTGT-A

Position:

• chr2-96254973-ACTGT-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.265_268del​(p.Thr89CysfsTer34) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

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

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• 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]. Clinvar id is 126966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.265_268del	p.Thr89CysfsTer34	frameshift_variant	3/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.265_268del	p.Thr89CysfsTer34	frameshift_variant	3/4		NP_001180233.1
TMEM127	NM_001407282.1	c.13_16del	p.Thr5CysfsTer34	frameshift_variant	2/3		NP_001394211.1
TMEM127	NM_001407283.1	c.13_16del	p.Thr5CysfsTer34	frameshift_variant	2/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.265_268del	p.Thr89CysfsTer34	frameshift_variant	3/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.265_268del	p.Thr89CysfsTer34	frameshift_variant	3/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.13_16del	p.Thr5CysfsTer34	frameshift_variant	2/3	3		ENSP00000411810

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

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 27, 2023	- -
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

Sep 04, 2020

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 PGL/PCC syndrome (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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2019

For these reasons, this variant has been classified as Pathogenic. 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. 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). 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.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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908822; hg19: chr2-96920711;