Variant 2-96254107-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_017849.4(TMEM127):c.418T>C(p.Cys140Arg) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C140F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.75

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity TM127_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_017849.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-96254106-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 2-96254107-A-G is Pathogenic according to our data. Variant chr2-96254107-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126970.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-96254107-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM127	NM_017849.4 linkuse as main transcript	c.418T>C	p.Cys140Arg	missense_variant	4/4	ENST00000258439.8
TMEM127	NM_001193304.3 linkuse as main transcript	c.418T>C	p.Cys140Arg	missense_variant	4/4
TMEM127	NM_001407282.1 linkuse as main transcript	c.166T>C	p.Cys56Arg	missense_variant	3/3
TMEM127	NM_001407283.1 linkuse as main transcript	c.166T>C	p.Cys56Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TMEM127	ENST00000258439.8 linkuse as main transcript	c.418T>C	p.Cys140Arg	missense_variant	4/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.418T>C	p.Cys140Arg	missense_variant	4/4	1		P1
TMEM127	ENST00000435268.1 linkuse as main transcript	c.166T>C	p.Cys56Arg	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pheochromocytoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Familial Cancer Clinic, Veneto Institute of Oncology

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.85

.;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.035

MutationAssessor

Uncertain

2.0

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.96

MutPred

0.80

Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);.;

MVP

0.82

MPC

1.7

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.99

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