NM_019022.5:c.890A>G

Variant names:

• chr18-68682940-T-C
• rs1055129974
• NM_019022.5:c.890A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019022.5(TMX3):​c.890A>G​(p.Asn297Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TMX3 NM_019022.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33539018).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	NM_019022.5	MANE Select	c.890A>G	p.Asn297Ser	missense	Exon 13 of 16	NP_061895.3
	TMX3	NM_001350514.2		c.809A>G	p.Asn270Ser	missense	Exon 12 of 15	NP_001337443.1
	TMX3	NM_001350515.2		c.467A>G	p.Asn156Ser	missense	Exon 12 of 15	NP_001337444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	ENST00000299608.7	TSL:1 MANE Select	c.890A>G	p.Asn297Ser	missense	Exon 13 of 16	ENSP00000299608.2	Q96JJ7-1
	TMX3	ENST00000564631.5	TSL:1	n.*574A>G		non_coding_transcript_exon	Exon 12 of 15	ENSP00000456587.1	H3BVI1
	TMX3	ENST00000564631.5	TSL:1	n.*574A>G		3_prime_UTR	Exon 12 of 15	ENSP00000456587.1	H3BVI1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458182 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725472

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 85832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109818

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.17
Sift	Benign	0.087	T
Sift4G	Benign	0.13	T
Polyphen		0.92	P
Vest4		0.33
MutPred		0.56		Loss of helix (P = 0.0376)
MVP		0.26
MPC		0.73
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.70
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs1055129974; hg19: chr18-66350177;