rs1553436874

chr2-96253992-T-TA

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.532_533insT(p.Tyr178LeufsTer48) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y178Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.75

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. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96253992-T-TA is Pathogenic according to our data. Variant chr2-96253992-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM127	NM_017849.4	c.532_533insT	p.Tyr178LeufsTer48	frameshift_variant	4/4	ENST00000258439.8
TMEM127	NM_001193304.3	c.532_533insT	p.Tyr178LeufsTer48	frameshift_variant	4/4
TMEM127	NM_001407282.1	c.280_281insT	p.Tyr94LeufsTer48	frameshift_variant	3/3
TMEM127	NM_001407283.1	c.280_281insT	p.Tyr94LeufsTer48	frameshift_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8	c.532_533insT	p.Tyr178LeufsTer48	frameshift_variant	4/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1	c.532_533insT	p.Tyr178LeufsTer48	frameshift_variant	4/4	1		P1
TMEM127	ENST00000435268.1	c.280_281insT	p.Tyr94LeufsTer48	frameshift_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2023

Published functional studies demonstrate a damaging effect: variant results in diffuse subcellular localization and significantly reduced protein expression (Deng et al., 2017; Deng et al., 2018; Flores et al., 2020); Frameshift variant predicted to result in protein truncation, as the last 61 amino acids are replaced with 47 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28384794, 28855235, 32575117, 21156949, 29547888) -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2021

This sequence change creates a premature translational stop signal (p.Tyr178Leufs*48) in the TMEM127 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the TMEM127 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 28855235; Invitae). ClinVar contains an entry for this variant (Variation ID: 421874). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TMEM127 function (PMID: 28855235). This variant disrupts the C-terminus of the TMEM127 protein. Other variant(s) that disrupt this region (p.Ala186Argfs*44) have been observed in individuals with TMEM127-related conditions (PMID: 28384794). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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: rs1553436874; hg19: chr2-96919730;