2-96265329-G-A

Position:

chr2-96265329-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000258439.8(TMEM127):c.53C>T(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,520,940 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

TMEM127
ENST00000258439.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.44

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051310062).

BP6

Variant 2-96265329-G-A is Benign according to our data. Variant chr2-96265329-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000525 (80/152290) while in subpopulation EAS AF= 0.00983 (51/5188). AF 95% confidence interval is 0.00768. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMEM127	NM_017849.4 linkuse as main transcript	c.53C>T	p.Pro18Leu	missense_variant	2/4	ENST00000258439.8	NP_060319.1
TMEM127	NM_001193304.3 linkuse as main transcript	c.53C>T	p.Pro18Leu	missense_variant	2/4		NP_001180233.1
TMEM127	NM_001407283.1 linkuse as main transcript	c.-9+540C>T		intron_variant			NP_001394212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM127	ENST00000258439.8 linkuse as main transcript	c.53C>T	p.Pro18Leu	missense_variant	2/4	1	NM_017849.4	ENSP00000258439	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.53C>T	p.Pro18Leu	missense_variant	2/4	1		ENSP00000416660	P1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00980

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000911

AC:

112

AN:

122936

Hom.:

AF XY:

0.000842

AC XY:

AN XY:

67734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.000325

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000216

Gnomad OTH exome

AF:

0.000531

GnomAD4 exome

AF:

0.000245

AC:

335

AN:

1368650

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

166

AN XY:

674116

show subpopulations

Gnomad4 AFR exome

AF:

0.000131

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00608

Gnomad4 SAS exome

AF:

0.000562

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000467

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000525

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00983

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Bravo

AF:

0.000491

ExAC

AF:

0.000229

AC:

Asia WGS

AF:

0.00839

AC:

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pheochromocytoma

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 23, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 29, 2021

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.19

Sift

Benign

0.17

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.073

B;B

Vest4

0.14

MutPred

0.14

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.38

MPC

0.42

ClinPred

0.024

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.63

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