2-96253953-G-A

Position:

chr2-96253953-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_017849.4(TMEM127):c.572C>T(p.Thr191Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

TMEM127
NM_017849.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.39

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 -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0155994).

BP6

Variant 2-96253953-G-A is Benign according to our data. Variant chr2-96253953-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 486539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM127	NM_017849.4 linkuse as main transcript	c.572C>T	p.Thr191Met	missense_variant	4/4	ENST00000258439.8
TMEM127	NM_001193304.3 linkuse as main transcript	c.572C>T	p.Thr191Met	missense_variant	4/4
TMEM127	NM_001407282.1 linkuse as main transcript	c.320C>T	p.Thr107Met	missense_variant	3/3
TMEM127	NM_001407283.1 linkuse as main transcript	c.320C>T	p.Thr107Met	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TMEM127	ENST00000258439.8 linkuse as main transcript	c.572C>T	p.Thr191Met	missense_variant	4/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1 linkuse as main transcript	c.572C>T	p.Thr191Met	missense_variant	4/4	1		P1
TMEM127	ENST00000435268.1 linkuse as main transcript	c.320C>T	p.Thr107Met	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000895

AC:

225

AN:

251442

Hom.:

AF XY:

0.000861

AC XY:

117

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00980

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000309

AC:

451

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00796

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152246

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000873

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 23, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 23, 2023

- -

Hereditary pheochromocytoma-paraganglioma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

0.55

N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.86

MVP

0.86

MPC

1.3

ClinPred

0.13

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.89

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