rs1913578842

Variant names:

• chr18-68682926-C-A
• rs1913578842
• NM_019022.5:c.904G>T

Your query was ambiguous. Multiple possible variants found:

• chr18-68682926-C-A
• chr18-68682926-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019022.5(TMX3):​c.904G>T​(p.Asp302Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000688 in 1,453,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D302H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMX3 NM_019022.5 missense, splice_region
• Scores: Splicing: ADA: 0.9896
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.21
• 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 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	c.904G>T	p.Asp302Tyr	missense_variant, splice_region_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.904G>T	p.Asp302Tyr	missense_variant, splice_region_variant	Exon 13 of 16	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*588G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 15	1		ENSP00000456587.1
TMX3	ENST00000564631.5	n.*588G>T		3_prime_UTR_variant	Exon 12 of 15	1		ENSP00000456587.1
TMX3	ENST00000578765.1	n.479G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453526 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723168

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39268

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107260

Other (OTH) AF: 0.00 AC: 0 AN: 60006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.2
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.20
Sift	Benign	0.036	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.53		Gain of catalytic residue at D302 (P = 0.0255);
MVP		0.28
MPC		1.0
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.68
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.060		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: rs1913578842; hg19: chr18-66350163;