chr18-68682937-G-T

Variant names:

• chr18-68682937-G-T
• NM_019022.5:c.893C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019022.5(TMX3):​c.893C>A​(p.Thr298Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMX3 NM_019022.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07777935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5	c.893C>A	p.Thr298Asn	missense_variant	Exon 13 of 16	ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.893C>A	p.Thr298Asn	missense_variant	Exon 13 of 16	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*577C>A		non_coding_transcript_exon_variant	Exon 12 of 15	1		ENSP00000456587.1
TMX3	ENST00000564631.5	n.*577C>A		3_prime_UTR_variant	Exon 12 of 15	1		ENSP00000456587.1
TMX3	ENST00000578765.1	n.468C>A		non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.893C>A (p.T298N) alteration is located in exon 13 (coding exon 13) of the TMX3 gene. This alteration results from a C to A substitution at nucleotide position 893, causing the threonine (T) at amino acid position 298 to be replaced by an asparagine (N). 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	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		3.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.040
Sift	Benign	0.082	T
Sift4G	Benign	0.21	T
Polyphen		0.0030	B
Vest4		0.21
MutPred		0.42		Loss of helix (P = 0.0626);
MVP		0.13
MPC		0.31
ClinPred		0.57	D
GERP RS		3.6
Varity_R		0.040
gMVP		0.59
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

hg19: chr18-66350174;