rs1060500598

Positions:

• chr2-96253854-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_017849.4(TMEM127):​c.671A>G​(p.Tyr224Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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, single submitter U:1
• Conservation: PhyloP100: 7.51

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.671A>G	p.Tyr224Cys	missense_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.671A>G	p.Tyr224Cys	missense_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.419A>G	p.Tyr140Cys	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.419A>G	p.Tyr140Cys	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.671A>G	p.Tyr224Cys	missense_variant	4/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.671A>G	p.Tyr224Cys	missense_variant	4/4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.419A>G	p.Tyr140Cys	missense_variant	3/3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TMEM127-related disease. This sequence change replaces tyrosine with cysteine at codon 224 of the TMEM127 protein (p.Tyr224Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0020	B;B;.
Vest4		0.73
MutPred		0.29		Loss of phosphorylation at Y224 (P = 0.0042);Loss of phosphorylation at Y224 (P = 0.0042);.;
MVP		0.72
MPC		1.4
ClinPred		0.87	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1060500598; hg19: chr2-96919592;