18-68691247-C-T

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.637+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,326,834 control chromosomes in the GnomAD database, including 1,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (848 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (646 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.160

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=-0.89).
• BP6: Variant 18-68691247-C-T is Benign according to our data. Variant chr18-68691247-C-T is described in ClinVar as [Benign]. Clinvar id is 1280904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.637+48G>A		intron_variant		ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.637+48G>A		intron_variant		1	NM_019022.5	P1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9108 AN: 151860 Hom.: 841 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.0537

GnomAD3 exomes AF: 0.0168 AC: 2877 AN: 171102 Hom.: 231 AF XY: 0.0132 AC XY: 1213 AN XY: 91746

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.00705

Gnomad EAS exome AF: 0.0000739

Gnomad SAS exome AF: 0.000679

Gnomad FIN exome AF: 0.000109

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00765 AC: 8982 AN: 1174854 Hom.: 646 Cov.: 14 AF XY: 0.00696 AC XY: 4088 AN XY: 587598

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.00752

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000690

Gnomad4 FIN exome AF: 0.0000815

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0601 AC: 9129 AN: 151980 Hom.: 848 Cov.: 32 AF XY: 0.0588 AC XY: 4366 AN XY: 74300

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000284

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0281 Hom.: 65

Bravo AF: 0.0696

Asia WGS AF: 0.0100 AC: 37 AN: 3462

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.6
Dann	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs309227; hg19: chr18-66358484;