18-68687906-GCATA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_019022.5(TMX3):c.638-145_638-142del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 512,326 control chromosomes in the GnomAD database, including 528 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (424 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (104 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.433

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 -10 ACMG points.

• BP6: Variant 18-68687906-GCATA-G is Benign according to our data. Variant chr18-68687906-GCATA-G is described in ClinVar as [Benign]. Clinvar id is 1178895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.638-145_638-142del		intron_variant		ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.638-145_638-142del		intron_variant		1	NM_019022.5	P1
TMX3	ENST00000564631.5	c.*322-145_*322-142del		intron_variant, NMD_transcript_variant		1
TMX3	ENST00000578765.1	n.68_71del		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6301 AN: 151874 Hom.: 420 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0331

GnomAD4 exome AF: 0.00493 AC: 1775 AN: 360336 Hom.: 104 AF XY: 0.00419 AC XY: 782 AN XY: 186676

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0129

Gnomad4 ASJ exome AF: 0.00503

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000399

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000407

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0416 AC: 6318 AN: 151990 Hom.: 424 Cov.: 32 AF XY: 0.0402 AC XY: 2985 AN XY: 74296

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0328

Alfa AF: 0.0316 Hom.: 25

Bravo AF: 0.0472

Asia WGS AF: 0.00665 AC: 23 AN: 3474

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 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs33920607; hg19: chr18-66355143;