2-96254933-GC-G

Position:

• chr2-96254933-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000258439.8(TMEM127):​c.308del​(p.Gly103AlafsTer21) 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. G103G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 ENST00000258439.8 frameshift
• Clinical Significance: Likely 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 Pathogenic. Variant got 12 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 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96254933-GC-G is Pathogenic according to our data. Variant chr2-96254933-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 165445.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-96254933-GC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.308del	p.Gly103AlafsTer21	frameshift_variant	3/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.308del	p.Gly103AlafsTer21	frameshift_variant	3/4		NP_001180233.1
TMEM127	NM_001407282.1	c.56del	p.Gly19AlafsTer21	frameshift_variant	2/3		NP_001394211.1
TMEM127	NM_001407283.1	c.56del	p.Gly19AlafsTer21	frameshift_variant	2/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.308del	p.Gly103AlafsTer21	frameshift_variant	3/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.308del	p.Gly103AlafsTer21	frameshift_variant	3/4	1		ENSP00000416660	P1
TMEM127	ENST00000435268.1	c.56del	p.Gly19AlafsTer21	frameshift_variant	2/3	3		ENSP00000411810

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2016

The p.Gly103fs variant in TMEM127 has been identified in 1 individual with pheoc hromocytomas and renal cell carcinoma (Hernandez 2015, LMM data). It has not be en identified in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 103 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Multiple heterozygous variants in TMEM127 leading to a frameshift and predicted truncate d or absent protein have been reported in individuals with pheochromocytomas. In summary, although additional studies are required to fully establish its clinic al significance, the p.Gly103fs variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727503490; hg19: chr2-96920671;