chr2-96253884-A-ATCTCTGAGAGCAGC

Variant names:

• chr2-96253884-A-ATCTCTGAGAGCAGC
• rs121908831
• NM_017849.4:c.627_640dupGCTGCTCTCAGAGA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_017849.4(TMEM127):​c.627_640dupGCTGCTCTCAGAGA​(p.Met214SerfsTer98) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.51
• Publications: 1 publications found

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]

TMEM127 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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. Fraction of 0.107 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 2-96253884-A-ATCTCTGAGAGCAGC is Pathogenic according to our data. Variant chr2-96253884-A-ATCTCTGAGAGCAGC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126973.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.627_640dupGCTGCTCTCAGAGA	p.Met214SerfsTer98	frameshift_variant	Exon 4 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.627_640dupGCTGCTCTCAGAGA	p.Met214SerfsTer98	frameshift_variant	Exon 4 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.375_388dupGCTGCTCTCAGAGA	p.Met130SerfsTer98	frameshift_variant	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.375_388dupGCTGCTCTCAGAGA	p.Met130SerfsTer98	frameshift_variant	Exon 3 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.627_640dupGCTGCTCTCAGAGA	p.Met214SerfsTer98	frameshift_variant	Exon 4 of 4	1	NM_017849.4	ENSP00000258439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pheochromocytoma Pathogenic:1

-

Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908831; hg19: chr2-96919622;