Genetic Variant TMEM127:p.Ala3Asp (chr2-96265374-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017849.4(TMEM127):c.8C>A(p.Ala3Asp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.78

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23358741).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM127	NM_017849.4 link	c.8C>A	p.Ala3Asp	missense_variant	Exon 2 of 4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_001193304.3 link	c.8C>A	p.Ala3Asp	missense_variant	Exon 2 of 4		NP_001180233.1	O75204
TMEM127	NM_001407283.1 link	c.-9+495C>A		intron_variant	Intron 1 of 2		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 link	c.8C>A	p.Ala3Asp	missense_variant	Exon 2 of 4	1	NM_017849.4	ENSP00000258439.3		O75204

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1308534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

642050

African (AFR)

AF:

0.00

AC:

AN:

26848

American (AMR)

AF:

0.00

AC:

AN:

25858

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20476

East Asian (EAS)

AF:

0.00

AC:

AN:

32176

South Asian (SAS)

AF:

0.00

AC:

AN:

68192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3806

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045358

Other (OTH)

AF:

0.00

AC:

AN:

54324

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Feb 29, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A3D variant (also known as c.8C>A), located in coding exon 1 of the TMEM127 gene, results from a C to A substitution at nucleotide position 8. The alanine at codon 3 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

T;T

Eigen

Benign

-0.019

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.47

.;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

0.69

N;N

PhyloP100

5.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0070

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.22

MutPred

0.24

Loss of MoRF binding (P = 0.0584);Loss of MoRF binding (P = 0.0584);

MVP

0.84

MPC

0.63

ClinPred

0.90

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.82

Mutation Taster

=43/57

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over