chr18-68681214-C-T

Position:

• chr18-68681214-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000299608.7(TMX3):​c.906-104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,015,442 control chromosomes in the GnomAD database, including 6,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (4028 hom., cov: 33)
  • Exomes 𝑓: 0.023 (2268 hom.)
• Consequence: TMX3 ENST00000299608.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.450

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]

TMX3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-68681214-C-T is Benign according to our data. Variant chr18-68681214-C-T is described in ClinVar as [Benign]. Clinvar id is 1283002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX3	NM_019022.5	c.906-104G>A		intron_variant		ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.906-104G>A		intron_variant		1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*590-104G>A		intron_variant		1		ENSP00000456587.1
TMX3	ENST00000566135.1	n.30+79G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20171 AN: 152002 Hom.: 4020 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.0737

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0232 AC: 20002 AN: 863320 Hom.: 2268 Cov.: 11 AF XY: 0.0220 AC XY: 9334 AN XY: 423640

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.0460

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00412

Gnomad4 FIN exome AF: 0.00519

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0429

GnomAD4 genome AF: 0.133 AC: 20213 AN: 152122 Hom.: 4028 Cov.: 33 AF XY: 0.128 AC XY: 9494 AN XY: 74400

Gnomad4 AFR AF: 0.431

Gnomad4 AMR AF: 0.0685

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00600

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0651 Hom.: 465

Bravo AF: 0.152

Asia WGS AF: 0.0290 AC: 103 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.51
DANN	Benign	0.53

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: rs309209; hg19: chr18-66348451;