18-68676890-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019022.5(TMX3):c.*43A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,575,472 control chromosomes in the GnomAD database, including 1,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (851 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (807 hom.)
• Consequence: TMX3 NM_019022.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.236

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-68676890-T-C is Benign according to our data. Variant chr18-68676890-T-C is described in ClinVar as [Benign]. Clinvar id is 1251413.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.*43A>G		3_prime_UTR_variant	16/16	ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.*43A>G		3_prime_UTR_variant	16/16	1	NM_019022.5	P1
TMX3	ENST00000564631.5	c.*1092A>G		3_prime_UTR_variant, NMD_transcript_variant	15/15	1
TMX3	ENST00000578816.1	n.419A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9161 AN: 152130 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0368

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.0536

GnomAD3 exomes AF: 0.0184 AC: 4108 AN: 223866 Hom.: 358 AF XY: 0.0141 AC XY: 1708 AN XY: 120818

Gnomad AFR exome AF: 0.207

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.00818

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000567

Gnomad FIN exome AF: 0.0000501

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00751 AC: 10688 AN: 1423224 Hom.: 807 Cov.: 28 AF XY: 0.00678 AC XY: 4790 AN XY: 707002

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.00803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000625

Gnomad4 FIN exome AF: 0.0000774

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0603 AC: 9182 AN: 152248 Hom.: 851 Cov.: 32 AF XY: 0.0589 AC XY: 4387 AN XY: 74452

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.00899 Hom.: 28

Bravo AF: 0.0699

Asia WGS AF: 0.0100 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	13
Dann	Benign	0.84

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

LitVar

Other links and lift over

dbSNP: rs309204; hg19: chr18-66344127;