rs121908817

Positions:

• chr2-96265232-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000258439.8(TMEM127):​c.149_150insA​(p.Pro51AlafsTer57) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic,risk factor (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 ENST00000258439.8 frameshift
• Clinical Significance: Likely pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.26

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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96265232-C-CT is Pathogenic according to our data. Variant chr2-96265232-C-CT is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 110.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.149_150insA	p.Pro51AlafsTer57	frameshift_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.149_150insA	p.Pro51AlafsTer57	frameshift_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+636_-9+637insA		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.149_150insA	p.Pro51AlafsTer57	frameshift_variant	2/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.149_150insA	p.Pro51AlafsTer57	frameshift_variant	2/4	1		ENSP00000416660	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic; risk factor

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pheochromocytoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Familial Cancer Clinic, Veneto Institute of Oncology

-

- -

Pheochromocytoma, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2010

- -

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: rs121908817; hg19: chr2-96930970;