rs775944671

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017849.4(TMEM127):c.377C>T(p.Thr126Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T126A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM127	NM_017849.4 linkuse as main transcript	c.377C>T	p.Thr126Ile	missense_variant	3/4	ENST00000258439.8
TMEM127	NM_001193304.3 linkuse as main transcript	c.377C>T	p.Thr126Ile	missense_variant	3/4
TMEM127	NM_001407282.1 linkuse as main transcript	c.125C>T	p.Thr42Ile	missense_variant	2/3
TMEM127	NM_001407283.1 linkuse as main transcript	c.125C>T	p.Thr42Ile	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TMEM127	ENST00000258439.8 linkuse as main transcript	c.377C>T	p.Thr126Ile	missense_variant	3/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.377C>T	p.Thr126Ile	missense_variant	3/4	1		P1
TMEM127	ENST00000435268.1 linkuse as main transcript	c.125C>T	p.Thr42Ile	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251458

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2021

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 126 of the TMEM127 protein (p.Thr126Ile). This variant is present in population databases (rs775944671, gnomAD 0.003%). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 33051659). ClinVar contains an entry for this variant (Variation ID: 463844). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Experimental studies have shown that this missense change does not substantially affect TMEM127 function (PMID: 24334765). 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

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.30

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.3

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

1.1

N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.081

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.86

MutPred

0.37

Gain of methylation at K124 (P = 0.0723);Gain of methylation at K124 (P = 0.0723);.;

MVP

0.81

MPC

0.67

ClinPred

0.55

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over