2-96253884-A-ATCTCTGAGAGCAGC

Position:

• chr2-96253884-A-ATCTCTGAGAGCAGC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_017849.4(TMEM127):​c.627_640dupGCTGCTCTCAGAGA​(p.Met214fs) 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 (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

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 Likely_pathogenic. Variant got 7 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 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 126973.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.627_640dupGCTGCTCTCAGAGA	p.Met214fs	frameshift_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.627_640dupGCTGCTCTCAGAGA	p.Met214fs	frameshift_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.375_388dupGCTGCTCTCAGAGA	p.Met130fs	frameshift_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.375_388dupGCTGCTCTCAGAGA	p.Met130fs	frameshift_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.627_640dupGCTGCTCTCAGAGA	p.Met214fs	frameshift_variant	4/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.627_640dupGCTGCTCTCAGAGA	p.Met214fs	frameshift_variant	4/4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.375_388dupGCTGCTCTCAGAGA	p.Met130fs	frameshift_variant	3/3	3		ENSP00000411810.1

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

Likely pathogenic, no assertion criteria provided

literature only

Familial Cancer Clinic, Veneto Institute of Oncology

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908831; hg19: chr2-96919622;