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-T
• chr2-96265379-C-G

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS1_Moderate PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000664517: 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" and additional evidence is available in ClinVar.

• 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: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 24 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
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000664517: 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).; SCV005834055: Experimental studies have shown that disruption of the initiator codon affects TMEM127 function (PMID: 21156949).
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	NM_017849.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.3G>T	p.Met1?	start_lost	Exon 2 of 4	NP_001180233.1	O75204
	TMEM127	NM_001407283.1		c.-9+490G>T		intron	N/A	NP_001394212.1	C9J4H2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 2 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000910913.1		c.3G>T	p.Met1?	start_lost	Exon 1 of 3	ENSP00000580972.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary pheochromocytoma and paraganglioma (1)
1	-	-	not provided (1)
1	-	-	Pheochromocytoma (1)

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	0.99	D
MetaSVM	Uncertain	0.43	D
PhyloP100		4.1
PROVEAN	Benign	-0.91	N
REVEL	Pathogenic	0.66
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
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;