chr2-96254958-AC-A

Position:

• chr2-96254958-AC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_017849.4(TMEM127):​c.283delG​(p.Val95fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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, single submitter P:1
• Conservation: PhyloP100: 7.46

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 Likely_pathogenic. Variant got 8 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96254958-AC-A is Pathogenic according to our data. Variant chr2-96254958-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 463843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.283delG	p.Val95fs	frameshift_variant	3/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.283delG	p.Val95fs	frameshift_variant	3/4		NP_001180233.1
TMEM127	NM_001407282.1	c.31delG	p.Val11fs	frameshift_variant	2/3		NP_001394211.1
TMEM127	NM_001407283.1	c.31delG	p.Val11fs	frameshift_variant	2/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.283delG	p.Val95fs	frameshift_variant	3/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.283delG	p.Val95fs	frameshift_variant	3/4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.31delG	p.Val11fs	frameshift_variant	2/3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2017

For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (p.Gln157*) has been reported in individuals affected with pheochromocytoma and 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 not been reported in the literature in individuals with TMEM127-related disease. 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.Val95Serfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acids of the TMEM127 protein. -

Computational scores

Source: dbNSFP v4.3

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: rs1553437028; hg19: chr2-96920696;