rs1553437719

Positions:

• chr2-96265170-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_017849.4(TMEM127):​c.212T>A​(p.Val71Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Transmembrane protein 127 (size 237) in uniprot entity TM127_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_017849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.212T>A	p.Val71Glu	missense_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.212T>A	p.Val71Glu	missense_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+699T>A		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.212T>A	p.Val71Glu	missense_variant	2/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.212T>A	p.Val71Glu	missense_variant	2/4	1		ENSP00000416660.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2024

The p.V71E variant (also known as c.212T>A), located in coding exon 1 of the TMEM127 gene, results from a T to A substitution at nucleotide position 212. The valine at codon 71 is replaced by glutamic acid, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 463842). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 71 of the TMEM127 protein (p.Val71Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.96	D;D
Vest4		0.92
MutPred		0.49		Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);
MVP		0.82
MPC		1.2
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.55
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553437719; hg19: chr2-96930908;