Genetic Variant TMX3:c.906-104G>A (chr18-68681214-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019022.5(TMX3):c.906-104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,015,442 control chromosomes in the GnomAD database, including 6,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 4028 hom., cov: 33)

Exomes 𝑓: 0.023 ( 2268 hom. )

Consequence

TMX3
NM_019022.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.450

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 18-68681214-C-T is Benign according to our data. Variant chr18-68681214-C-T is described in ClinVar as Benign. ClinVar VariationId is 1283002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

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	Effect	Exon Rank	Protein
TMX3	NM_019022.5	MANE Select	c.906-104G>A	intron	N/A	NP_061895.3
TMX3	NM_001350514.2		c.825-104G>A	intron	N/A	NP_001337443.1
TMX3	NM_001350515.2		c.483-104G>A	intron	N/A	NP_001337444.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TMX3	ENST00000299608.7	TSL:1 MANE Select	c.906-104G>A	intron	N/A	ENSP00000299608.2	Q96JJ7-1
TMX3	ENST00000564631.5	TSL:1	n.*590-104G>A	intron	N/A	ENSP00000456587.1	H3BVI1
TMX3	ENST00000915516.1		c.1029-104G>A	intron	N/A	ENSP00000585575.1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20171

AN:

152002

Hom.:

4020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.431

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0688

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.0737

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.104

GnomAD4 exome

AF:

0.0232

AC:

20002

AN:

863320

Hom.:

2268

Cov.:

AF XY:

0.0220

AC XY:

9334

AN XY:

423640

show subpopulations

African (AFR)

AF:

0.460

AC:

8794

AN:

19124

American (AMR)

AF:

0.0460

AC:

575

AN:

12496

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

162

AN:

14120

East Asian (EAS)

AF:

0.00

AC:

AN:

27926

South Asian (SAS)

AF:

0.00412

AC:

115

AN:

27942

European-Finnish (FIN)

AF:

0.00519

AC:

146

AN:

28144

Middle Eastern (MID)

AF:

0.0321

AC:

AN:

2618

European-Non Finnish (NFE)

AF:

0.0123

AC:

8508

AN:

693254

Other (OTH)

AF:

0.0429

AC:

1618

AN:

37696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

733

1466

2200

2933

3666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.133

AC:

20213

AN:

152122

Hom.:

4028

Cov.:

AF XY:

0.128

AC XY:

9494

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.431

AC:

17867

AN:

41432

American (AMR)

AF:

0.0685

AC:

1048

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00600

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0828

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0132

AC:

898

AN:

67998

Other (OTH)

AF:

0.103

AC:

218

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

638

1276

1915

2553

3191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<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:

0.0752

Hom.:

654

Bravo

AF:

0.152

Asia WGS

AF:

0.0290

AC:

103

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.51

(source)

DANN

Benign

0.53

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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