NM_017849.4:c.149dupA

Variant names:

• chr2-96265232-C-CT
• rs121908817
• NM_017849.4:c.149dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_017849.4(TMEM127):​c.149dupA​(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). Synonymous variant affecting the same amino acid position (i.e. E50E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 frameshift
• Clinical Significance: Likely pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.26
• Publications: 2 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: Pathogenic. The variant received 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 VariationId is 110.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	NM_017849.4	MANE Select	c.149dupA	p.Pro51AlafsTer57	frameshift	Exon 2 of 4	NP_060319.1
	TMEM127	NM_001193304.3		c.149dupA	p.Pro51AlafsTer57	frameshift	Exon 2 of 4	NP_001180233.1
	TMEM127	NM_001407283.1		c.-9+636dupA		intron	N/A	NP_001394212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.149dupA	p.Pro51AlafsTer57	frameshift	Exon 2 of 4	ENSP00000258439.3
	TMEM127	ENST00000432959.2	TSL:1	c.149dupA	p.Pro51AlafsTer57	frameshift	Exon 2 of 4	ENSP00000416660.1
	TMEM127	ENST00000713754.1		n.149dupA		non_coding_transcript_exon	Exon 2 of 4	ENSP00000519055.1

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

Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Pheochromocytoma, susceptibility to Other:1

Mar 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908817; hg19: chr2-96930970;