Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000258439.8(TMEM127):c.556G>A(p.Ala186Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A186P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM127
ENST00000258439.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41

Publications

0 publications found

Variant links:

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]

TMEM127 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

TMEM127 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000258439.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM127	NM_017849.4	MANE Select	c.556G>A	p.Ala186Thr	missense	Exon 4 of 4	NP_060319.1
TMEM127	NM_001193304.3		c.556G>A	p.Ala186Thr	missense	Exon 4 of 4	NP_001180233.1
TMEM127	NM_001407282.1		c.304G>A	p.Ala102Thr	missense	Exon 3 of 3	NP_001394211.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.556G>A	p.Ala186Thr	missense	Exon 4 of 4	ENSP00000258439.3
TMEM127	ENST00000432959.2	TSL:1	c.556G>A	p.Ala186Thr	missense	Exon 4 of 4	ENSP00000416660.1
TMEM127	ENST00000435268.2	TSL:3	c.304G>A	p.Ala102Thr	missense	Exon 3 of 3	ENSP00000411810.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

0.55

PhyloP100

7.4

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.72

REVEL

Uncertain

0.53

Sift

Benign

0.47

Sift4G

Benign

0.13

Polyphen

0.99

Vest4

0.63

MutPred

0.31

Loss of helix (P = 0.0376)

MVP

0.83

MPC

1.0

ClinPred

0.79

GERP RS

5.9

Varity_R

0.089

gMVP

0.77

Mutation Taster

=22/78

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

2-96253969-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over