rs121908814

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-96265379-C-A
• chr2-96265379-C-G
• chr2-96265379-C-T

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>T​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000785 in 1,274,416 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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-A is Pathogenic according to our data. Variant chr2-96265379-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.3G>T	p.Met1?	start_lost	Exon 2 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.3G>T	p.Met1?	start_lost	Exon 2 of 4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+490G>T		intron_variant	Intron 1 of 2		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.3G>T	p.Met1?	start_lost	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.85e-7 AC: 1 AN: 1274416 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 624168

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0000158 AC: 1 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: 0.00 AC: 0 AN: 1028928

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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:1

-

Familial Cancer Clinic, Veneto Institute of Oncology

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jan 04, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in at least one patient with pheochromocytoma (Yao et al., 2010; Armaiz-Pena et al., 2021); This variant is associated with the following publications: (PMID: 32575117, 33051659, 21156949) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 06, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the TMEM127 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration was identified in a cohort of 990 individuals with a diagnosis of pheochromocytoma and/or paraganglioma in a woman with a benign adrenal tumor and acrocyanosis who did not have a family history of PGL. The authors created a GFP expression construct containing the predicted N-terminal truncation of 85 amino acids and found that it did not have the same cellular localization as wild type protein, suggesting impaired function (Yao L et al. JAMA. 2010 Dec;304:2611-9). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 syndromes (PMID: 28384794; internal data). ClinVar contains an entry for this variant (Variation ID: 126968). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID: 21156949). This variant disrupts a region of the TMEM127 protein in which other variant(s) (p.Ala47Asp) have been observed in individuals with TMEM127-related conditions (PMID: 20923864). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;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	0.99	D;D
MetaSVM	Uncertain	0.43	D
PhyloP100		4.1
PROVEAN	Benign	-0.91	N;N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0020	B;B
Vest4		0.94
MutPred		0.94		Loss of MoRF binding (P = 0.0982);Loss of MoRF binding (P = 0.0982);
MVP		0.80
ClinPred		0.99	D
GERP RS		5.7
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;