chr2-96265246-T-A

Position:

• chr2-96265246-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_017849.4(TMEM127):​c.136A>T​(p.Thr46Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 5.41

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 Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.32183886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.136A>T	p.Thr46Ser	missense_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.136A>T	p.Thr46Ser	missense_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1	c.-9+623A>T		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.136A>T	p.Thr46Ser	missense_variant	2/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1	c.136A>T	p.Thr46Ser	missense_variant	2/4	1		ENSP00000416660	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jul 26, 2019

The p.T46S variant (also known as c.136A>T), located in coding exon 1 of the TMEM127 gene, results from an A to T substitution at nucleotide position 136. The threonine at codon 46 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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

Aug 07, 2021

This sequence change replaces threonine with serine at codon 46 of the TMEM127 protein (p.Thr46Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TMEM127-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	.;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.26	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.34	B;B
Vest4		0.49
MutPred		0.56		Gain of disorder (P = 0.0736);Gain of disorder (P = 0.0736);
MVP		0.70
MPC		0.42
ClinPred		0.67	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.77

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: rs144659242; hg19: chr2-96930984;