18-68681091-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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

Publications

6 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 3040971.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019022.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMX3	NM_019022.5	MANE Select	c.925G>A	p.Val309Ile	missense	Exon 14 of 16	NP_061895.3
TMX3	NM_001350514.2		c.844G>A	p.Val282Ile	missense	Exon 13 of 15	NP_001337443.1
TMX3	NM_001350515.2		c.502G>A	p.Val168Ile	missense	Exon 13 of 15	NP_001337444.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMX3	ENST00000299608.7	TSL:1 MANE Select	c.925G>A	p.Val309Ile	missense	Exon 14 of 16	ENSP00000299608.2	Q96JJ7-1
TMX3	ENST00000564631.5	TSL:1	n.*609G>A		non_coding_transcript_exon	Exon 13 of 15	ENSP00000456587.1	H3BVI1
TMX3	ENST00000564631.5	TSL:1	n.*609G>A		3_prime_UTR	Exon 13 of 15	ENSP00000456587.1	H3BVI1

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

GnomAD2 exomes

AF:

0.00207

AC:

468

AN:

225738

AF XY:

0.00210

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 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

African (AFR)

AF:

0.000438

AC:

AN:

31976

American (AMR)

AF:

0.00294

AC:

112

AN:

38056

Ashkenazi Jewish (ASJ)

AF:

0.0000397

AC:

AN:

25200

East Asian (EAS)

AF:

0.00

AC:

AN:

38108

South Asian (SAS)

AF:

0.00202

AC:

156

AN:

77042

European-Finnish (FIN)

AF:

0.000153

AC:

AN:

52340

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00384

AC:

4201

AN:

1094646

Other (OTH)

AF:

0.00207

AC:

122

AN:

58810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

201

401

602

802

1003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152270

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41550

American (AMR)

AF:

0.00216

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68002

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00276

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

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TMX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

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

PhyloP100

1.1

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

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over