chr2-96254832-C-A

Position:

• chr2-96254832-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017849.4(TMEM127):​c.409+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.49

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.22873083 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 7, new splice context is: gccGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96254832-C-A is Pathogenic according to our data. Variant chr2-96254832-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.409+1G>T		splice_donor_variant, intron_variant		ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.409+1G>T		splice_donor_variant, intron_variant			NP_001180233.1
TMEM127	NM_001407282.1	c.157+1G>T		splice_donor_variant, intron_variant			NP_001394211.1
TMEM127	NM_001407283.1	c.157+1G>T		splice_donor_variant, intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.409+1G>T		splice_donor_variant, intron_variant		1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.409+1G>T		splice_donor_variant, intron_variant		1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.157+1G>T		splice_donor_variant, intron_variant		3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 27, 2022	- -
Likely pathogenic, no assertion criteria provided	literature only	Familial Cancer Clinic, Veneto Institute of Oncology	-	- -
Likely pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_017849.4:c.409+1G>T (chr2:96254832) in TMEM127 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2019

The c.409+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the TMEM127 gene. This mutation was identified in a 38 year-old Spanish woman with a benign adrenal pheochromocytoma/paraganglioma whose tumor demonstrated loss of heterozygosity (LOH) of the wild-type allele. Subsequent RNA analysis confirmed that this alteration results in in-frame skipping of exon 3 (coding exon 2), which is a large percentage of the protein (Yao L et al. JAMA, 2010 Dec;304:2611-9). This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908825; hg19: chr2-96920570;