NM_017849.4:c.52C>A

Variant names:

• chr2-96265330-G-T
• rs1452142786
• NM_017849.4:c.52C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017849.4(TMEM127):​c.52C>A​(p.Pro18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000731 in 1,368,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17598534).

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.52C>A	p.Pro18Thr	missense	Exon 2 of 4	NP_060319.1
	TMEM127	NM_001193304.3		c.52C>A	p.Pro18Thr	missense	Exon 2 of 4	NP_001180233.1
	TMEM127	NM_001407283.1		c.-9+539C>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.52C>A	p.Pro18Thr	missense	Exon 2 of 4	ENSP00000258439.3
	TMEM127	ENST00000432959.2	TSL:1	c.52C>A	p.Pro18Thr	missense	Exon 2 of 4	ENSP00000416660.1
	TMEM127	ENST00000713754.1		n.52C>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000519055.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1368612 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 674070

African (AFR) AF: 0.00 AC: 0 AN: 30568

American (AMR) AF: 0.00 AC: 0 AN: 34152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24574

East Asian (EAS) AF: 0.00 AC: 0 AN: 35070

South Asian (SAS) AF: 0.00 AC: 0 AN: 78228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4374

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070910

Other (OTH) AF: 0.00 AC: 0 AN: 57002

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P18T variant (also known as c.52C>A), located in coding exon 1 of the TMEM127 gene, results from a C to A substitution at nucleotide position 52. The proline at codon 18 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.0044
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.2
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.22	T
Sift4G	Benign	0.46	T
Polyphen		0.014	B
Vest4		0.26
MutPred		0.20		Gain of phosphorylation at P18 (P = 0.0017)
MVP		0.34
MPC		0.46
ClinPred		0.70	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.64
Mutation Taster		=77/23	polymorphism

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: rs1452142786; hg19: chr2-96931068;