11-57737996-A-G

Position:

chr11-57737996-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting

The ENST00000278422.9(TMX2):c.334A>G(p.Met112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,376 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

TMX2
ENST00000278422.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

TMX2 (HGNC:30739): (thioredoxin related transmembrane protein 2) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This protein is enriched on the mitochondria-associated-membrane of the ER via palmitoylation of two of its cytosolically exposed cysteines. [provided by RefSeq, Jan 2017]

TMX2 links:

ENSG00000288534 (HGNC:):

ENSG00000288534 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Thioredoxin-related transmembrane protein 2 (size 247) in uniprot entity TMX2_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in ENST00000278422.9

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04124987).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000857 (13/151652) while in subpopulation EAS AF= 0.00135 (7/5170). AF 95% confidence interval is 0.000635. There are 1 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX2	NM_015959.4 linkuse as main transcript	c.334A>G	p.Met112Val	missense_variant	3/8	ENST00000278422.9	NP_057043.1	Q9Y320-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMX2	ENST00000278422.9 linkuse as main transcript	c.334A>G	p.Met112Val	missense_variant	3/8	1	NM_015959.4	ENSP00000278422.4		Q9Y320-1
ENSG00000288534	ENST00000674060.1 linkuse as main transcript	n.103+328A>G		intron_variant				ENSP00000501055.2		A0A669KB09

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

151586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251288

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00130

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461724

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000781

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.0000857

AC:

AN:

151652

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74052

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.334A>G (p.M112V) alteration is located in exon 3 (coding exon 3) of the TMX2 gene. This alteration results from a A to G substitution at nucleotide position 334, causing the methionine (M) at amino acid position 112 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.060

Eigen

Benign

-0.075

Eigen_PC

Benign

0.086

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

M_CAP

Benign

0.0041

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.5

REVEL

Benign

0.046

Sift

Uncertain

0.019

Sift4G

Benign

0.084

Polyphen

0.053

Vest4

0.35

MVP

0.44

MPC

0.29

ClinPred

0.039

GERP RS

5.0

Varity_R

0.25

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