18-68682926-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_019022.5(TMX3):c.904G>C(p.Asp302His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000436 in 1,605,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TMX3
NM_019022.5 missense, splice_region

Scores

Splicing: ADA: 0.9880

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.21

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5 link	c.904G>C	p.Asp302His	missense_variant, splice_region_variant	Exon 13 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.904G>C	p.Asp302His	missense_variant, splice_region_variant	Exon 13 of 16	1	NM_019022.5	ENSP00000299608.2	Q96JJ7-1
TMX3	ENST00000564631.5 link	n.*588G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 15	1		ENSP00000456587.1	H3BVI1
TMX3	ENST00000564631.5 link	n.*588G>C		3_prime_UTR_variant	Exon 12 of 15	1		ENSP00000456587.1	H3BVI1
TMX3	ENST00000578765.1 link	n.479G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33184

American (AMR)

AF:

0.0000227

AC:

AN:

44102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

39268

South Asian (SAS)

AF:

0.00

AC:

AN:

85018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107260

Other (OTH)

AF:

0.0000667

AC:

AN:

60006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.0000656

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.904G>C (p.D302H) alteration is located in exon 13 (coding exon 13) of the TMX3 gene. This alteration results from a G to C substitution at nucleotide position 904, causing the aspartic acid (D) at amino acid position 302 to be replaced by a histidine (H). 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

0.18

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.014

MetaRNN

Benign

0.36

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

5.2

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.16

Sift

Benign

0.080

Sift4G

Uncertain

0.040

Polyphen

0.97

Vest4

0.33

MutPred

0.46

Loss of helix (P = 0.0626);

MVP

0.38

MPC

0.98

ClinPred

0.95

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.64

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

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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18-68682926-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over