rs1429621198

Positions:

• chr2-96253921-C-G
• chr2-96253921-C-T

Variant summary

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

The NM_017849.4(TMEM127):​c.604G>C​(p.Glu202Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 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.604G>C	p.Glu202Gln	missense_variant	4/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3	c.604G>C	p.Glu202Gln	missense_variant	4/4		NP_001180233.1
TMEM127	NM_001407282.1	c.352G>C	p.Glu118Gln	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1	c.352G>C	p.Glu118Gln	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8	c.604G>C	p.Glu202Gln	missense_variant	4/4	1	NM_017849.4	ENSP00000258439.3
TMEM127	ENST00000432959.1	c.604G>C	p.Glu202Gln	missense_variant	4/4	1		ENSP00000416660.1
TMEM127	ENST00000435268.1	c.352G>C	p.Glu118Gln	missense_variant	3/3	3		ENSP00000411810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.22	T;T;T
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.54
MutPred		0.35		Loss of disorder (P = 0.1208);Loss of disorder (P = 0.1208);.;
MVP		0.82
MPC		1.2
ClinPred		0.76	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96919659;