Variant rs117449369 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_019022.5(TMX3):c.925G>A(p.Val309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,574,074 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 15 hom. )

Consequence

TMX3
NM_019022.5 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.08

Variant links:

Genes affected

TMX3 (HGNC:24718): (thioredoxin related transmembrane protein 3) 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 canonical protein encoded by this gene has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and a C-terminal ER-retention sequence. This gene is expressed in many tissues but has its highest expression in heart and skeletal muscle. It is expressed in the retinal neuroepithelium and lens epithelium in the developing murine eye and haploinsufficiency of this gene in humans and zebrafish is associated with microphthalmia. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

TMX3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008639067).

BP6

Variant 18-68681091-C-T is Benign according to our data. Variant chr18-68681091-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3040971.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5 link	c.925G>A	p.Val309Ile	missense_variant	Exon 14 of 16	ENST00000299608.7	NP_061895.3	Q96JJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMX3	ENST00000299608.7 link	c.925G>A	p.Val309Ile	missense_variant	Exon 14 of 16	1	NM_019022.5	ENSP00000299608.2	Q96JJ7-1
TMX3	ENST00000564631.5 link	n.*609G>A		non_coding_transcript_exon_variant	Exon 13 of 15	1		ENSP00000456587.1	H3BVI1
TMX3	ENST00000564631.5 link	n.*609G>A		3_prime_UTR_variant	Exon 13 of 15	1		ENSP00000456587.1	H3BVI1
TMX3	ENST00000566135.1 link	n.50G>A		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00321

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00207

AC:

468

AN:

225738

Hom.:

AF XY:

0.00210

AC XY:

257

AN XY:

122452

show subpopulations

Gnomad AFR exome

AF:

0.000669

Gnomad AMR exome

AF:

0.00288

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00233

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.00286

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00325

AC:

4616

AN:

1421804

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

2276

AN XY:

705310

show subpopulations

Gnomad4 AFR exome

AF:

0.000438

Gnomad4 AMR exome

AF:

0.00294

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00202

Gnomad4 FIN exome

AF:

0.000153

Gnomad4 NFE exome

AF:

0.00384

Gnomad4 OTH exome

AF:

0.00207

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152270

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.00296

Hom.:

Bravo

AF:

0.00224

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00198

AC:

241

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TMX3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.0085

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.75

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

PrimateAI

Benign

0.31

PROVEAN

Benign

0.47

REVEL

Benign

0.064

Sift

Benign

0.89

Sift4G

Benign

0.74

Polyphen

0.0010

Vest4

0.20

MVP

0.34

MPC

0.22

ClinPred

0.011

GERP RS

4.9

Varity_R

0.013

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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