18-68687521-A-G

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.736+146T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,417,060 control chromosomes in the GnomAD database, including 10,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (5811 hom., cov: 33)
  • Exomes 𝑓: 0.026 (4391 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.30

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=-0.91).
• BP6: Variant 18-68687521-A-G is Benign according to our data. Variant chr18-68687521-A-G is described in ClinVar as [Benign]. Clinvar id is 1276569.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.736+146T>C		intron_variant		ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.736+146T>C		intron_variant		1	NM_019022.5	P1
TMX3	ENST00000564631.5	c.*420+146T>C		intron_variant, NMD_transcript_variant		1
TMX3	ENST00000578765.1	n.311+146T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24235 AN: 152064 Hom.: 5785 Cov.: 33

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0813

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.0259 AC: 32716 AN: 1264878 Hom.: 4391 Cov.: 30 AF XY: 0.0244 AC XY: 15046 AN XY: 616036

Gnomad4 AFR exome AF: 0.544

Gnomad4 AMR exome AF: 0.0590

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.0180

Gnomad4 SAS exome AF: 0.00709

Gnomad4 FIN exome AF: 0.00432

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0499

GnomAD4 genome AF: 0.160 AC: 24314 AN: 152182 Hom.: 5811 Cov.: 33 AF XY: 0.153 AC XY: 11415 AN XY: 74410

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.0810

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.0156

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.124

Alfa AF: 0.100 Hom.: 416

Bravo AF: 0.182

Asia WGS AF: 0.0560 AC: 198 AN: 3476

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 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	12
Dann	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs309221; hg19: chr18-66354758;