rs121908816

Positions:

• chr2-96265261-TAGAC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_017849.4(TMEM127):​c.117_120delGTCT​(p.Ile41fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000164 in 1,587,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TMEM127 NM_017849.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 6.95

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-96265261-TAGAC-T is Pathogenic according to our data. Variant chr2-96265261-TAGAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 397511.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.117_120delGTCT	p.Ile41fs	frameshift_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.117_120delGTCT	p.Ile41fs	frameshift_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+604_-9+607delGTCT		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.117_120delGTCT	p.Ile41fs	frameshift_variant	2/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.117_120delGTCT	p.Ile41fs	frameshift_variant	2/4	1		ENSP00000416660.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000150 AC: 3 AN: 200316 Hom.: 0 AF XY: 0.0000181 AC XY: 2 AN XY: 110606

Gnomad AFR exome AF: 0.0000871

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000224

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 23 AN: 1435170 Hom.: 0 AF XY: 0.0000126 AC XY: 9 AN XY: 712814

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000172

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Familial Cancer Clinic, Veneto Institute of Oncology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 12, 2016	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 10-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2024	The c.117_120delGTCT pathogenic mutation, located in coding exon 1 of the TMEM127 gene, results from a deletion of 4 nucleotides at nucleotide positions 117 to 120, causing a translational frameshift with a predicted alternate stop codon (p.I41Rfs*39). This alteration has been identified in individuals diagnosed with paragangliomas and/or pheochromocytomas (Takeichi N et al. Clin. Endocrinol. (Oxf), 2012 Nov;77:707-14; Yao L et al. JAMA, 2010 Dec;304:2611-9). Of note, this alteration is also known as c.116_119delTGTC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change creates a premature translational stop signal (p.Ile41Argfs*39) in the TMEM127 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM127 are known to be pathogenic (PMID: 20154675, 21156949). This variant is present in population databases (rs121908816, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with adrenal pheochromocytoma (PMID: 21156949, 22541004). This variant is also known as c.116_119delTGTC. ClinVar contains an entry for this variant (Variation ID: 397511). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2022	Variant summary: TMEM127 c.117_120delGTCT (p.Ile41ArgfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.5e-05 in 200316 control chromosomes (gnomAD). c.117_120delGTCT has been reported in the literature in multiple individuals with pheochromocytomas (e.g.Yao_2010, Takeichi_2012, Curras_Freixes_2015, Armaiz-Pena_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

TMEM127-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

The TMEM127 c.117_120delGTCT variant is predicted to result in a frameshift and premature protein termination (p.Ile41Argfs*39). In the literature, this variant is also reported as c.116_119delGTCT and c.115_118delCTGT. This variant was reported in multiple individuals with pheochromocytoma (Yao et al. 2010. PubMed ID: 21156949; Lima et al. 2023. PubMed ID: 37529773; Table S1, Currás-Freixes et al. 2015. PubMed ID: 26269449). Of note, one of those individuals also had a TP53 variant and breast and pancreatic cancers (Lima et al 2023. PubMed ID: 37529773). This variant is reported in 0.0050% of alleles in individuals of African descent in gnomAD. Frameshift variants in TMEM127 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37529773, 26269449, 28973655, 21156949, 37358160, 34906458, 22541004, 33051659) -

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: rs121908816; hg19: chr2-96930999;