2-96254031-T-C

Position:

chr2-96254031-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP5BP4BS2

The NM_017849.4(TMEM127):c.494A>G(p.His165Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.51

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 Likely_benign. Variant got -2 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

PP5

Variant 2-96254031-T-C is Pathogenic according to our data. Variant chr2-96254031-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241224.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.17309025). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM127	NM_017849.4 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	4/4	ENST00000258439.8	NP_060319.1	O75204
TMEM127	NM_001193304.3 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	4/4		NP_001180233.1	O75204
TMEM127	NM_001407282.1 linkuse as main transcript	c.242A>G	p.His81Arg	missense_variant	3/3		NP_001394211.1
TMEM127	NM_001407283.1 linkuse as main transcript	c.242A>G	p.His81Arg	missense_variant	3/3		NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	4/4	1	NM_017849.4	ENSP00000258439.3	O75204
TMEM127	ENST00000432959.1 linkuse as main transcript	c.494A>G	p.His165Arg	missense_variant	4/4	1		ENSP00000416660.1	O75204
TMEM127	ENST00000435268.1 linkuse as main transcript	c.242A>G	p.His81Arg	missense_variant	3/3	3		ENSP00000411810.1	C9J4H2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152112

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:

0.000576

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251486

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000576

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2024

The p.H165R variant (also known as c.494A>G), located in coding exon 3 of the TMEM127 gene, results from an A to G substitution at nucleotide position 494. The histidine at codon 165 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary pheochromocytoma-paraganglioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 165 of the TMEM127 protein (p.His165Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TMEM127-related conditions. ClinVar contains an entry for this variant (Variation ID: 241224). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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

Uncertain

0.37

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

T;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.070

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.39

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.96

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.96

D;D;.

Vest4

0.65

MutPred

0.19

Loss of ubiquitination at K162 (P = 0.0431);Loss of ubiquitination at K162 (P = 0.0431);.;

MVP

0.82

MPC

0.87

ClinPred

0.17

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.81

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

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