2-96265246-T-G

Variant names:

• chr2-96265246-T-G
• rs144659242
• NM_017849.4:c.136A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_017849.4(TMEM127):​c.136A>C​(p.Thr46Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,443,154 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T46A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 46 uncertain in NM_017849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

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.136A>C	p.Thr46Pro	missense	Exon 2 of 4	NP_060319.1
	TMEM127	NM_001193304.3		c.136A>C	p.Thr46Pro	missense	Exon 2 of 4	NP_001180233.1
	TMEM127	NM_001407283.1		c.-9+623A>C		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.136A>C	p.Thr46Pro	missense	Exon 2 of 4	ENSP00000258439.3
	TMEM127	ENST00000432959.2	TSL:1	c.136A>C	p.Thr46Pro	missense	Exon 2 of 4	ENSP00000416660.1
	TMEM127	ENST00000713754.1		n.136A>C		non_coding_transcript_exon	Exon 2 of 4	ENSP00000519055.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443154 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717190

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 43108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39102

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106882

Other (OTH) AF: 0.00 AC: 0 AN: 59782

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

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T46P variant (also known as c.136A>C), located in coding exon 1 of the TMEM127 gene, results from an A to C substitution at nucleotide position 136. The threonine at codon 46 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.058	T
Polyphen		0.96	D
Vest4		0.69
MutPred		0.57		Loss of helix (P = 0.0558)
MVP		0.78
MPC		0.84
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.96
Mutation Taster		=18/82	disease causing

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: rs144659242; hg19: chr2-96930984;