2-96253975-C-T

Variant names:

• chr2-96253975-C-T
• rs1060500597
• NM_017849.4:c.550G>A

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.550G>A​(p.Gly184Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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, single submitter U:1
• Conservation: PhyloP100: 7.41

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 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, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4	c.550G>A	p.Gly184Ser	missense_variant	Exon 4 of 4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.550G>A	p.Gly184Ser	missense_variant	Exon 4 of 4		NP_001180233.1
TMEM127	NM_001407282.1	c.298G>A	p.Gly100Ser	missense_variant	Exon 3 of 3		NP_001394211.1
TMEM127	NM_001407283.1	c.298G>A	p.Gly100Ser	missense_variant	Exon 3 of 3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.550G>A	p.Gly184Ser	missense_variant	Exon 4 of 4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.550G>A	p.Gly184Ser	missense_variant	Exon 4 of 4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.298G>A	p.Gly100Ser	missense_variant	Exon 3 of 3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 184 of the TMEM127 protein (p.Gly184Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 958007). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.014	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.86
MutPred		0.69		Gain of glycosylation at G184 (P = 0.0165);Gain of glycosylation at G184 (P = 0.0165);.;
MVP		0.91
MPC		1.3
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.92

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: rs1060500597; hg19: chr2-96919713;