2-96265379-C-T

Variant names:

• chr2-96265379-C-T
• rs121908814
• NM_017849.4:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_017849.4(TMEM127):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000021 in 1,426,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: TMEM127 NM_017849.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.07
• 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 53 pathogenic variants. Next in-frame start position is after 85 codons. Genomic position: 96254989. Lost 0.353 part of the original CDS.
• PS1: Another start lost variant in NM_017849.4 (TMEM127) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-96265379-C-T is Pathogenic according to our data. Variant chr2-96265379-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 532514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.3G>A	p.Met1?	start_lost	Exon 2 of 4	NP_060319.1
	TMEM127	NM_001193304.3		c.3G>A	p.Met1?	start_lost	Exon 2 of 4	NP_001180233.1
	TMEM127	NM_001407283.1		c.-9+490G>A		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.3G>A	p.Met1?	start_lost	Exon 2 of 4	ENSP00000258439.3
	TMEM127	ENST00000432959.2	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 4	ENSP00000416660.1
	TMEM127	ENST00000713754.1		n.3G>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000519055.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000157 AC: 2 AN: 1274416 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 624168

African (AFR) AF: 0.00 AC: 0 AN: 25366

American (AMR) AF: 0.00 AC: 0 AN: 20642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19176

East Asian (EAS) AF: 0.00 AC: 0 AN: 29680

South Asian (SAS) AF: 0.00 AC: 0 AN: 63436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3664

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1028928

Other (OTH) AF: 0.00 AC: 0 AN: 52674

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 06, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the TMEM127 gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This mutation has been reported in multiple individuals with pheochromocytomas (PCC) (Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212). This mutation has also been identified in the homozygous state in a Turkish patient with bilateral PCC (Eijkelenkamp K et al. Clin GEnet. 2018 May;93(5):1049-1056). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Feb 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID: 21156949). This sequence change affects the initiator methionine of the TMEM127 mRNA. The next in-frame methionine is located at codon 85. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 28384794, 29282712; Invitae). ClinVar contains an entry for this variant (Variation ID: 532514). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.43	D
PhyloP100		4.1
PROVEAN	Benign	-0.91	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.94
MutPred		0.94		Loss of MoRF binding (P = 0.0982)
MVP		0.80
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.73
Mutation Taster		=1/199	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: rs121908814; hg19: chr2-96931117;