18-68684314-T-A

Position:

• chr18-68684314-T-A

Variant summary

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

The NM_019022.5(TMX3):​c.795-71A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,492,968 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (105 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0600

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 18-68684314-T-A is Benign according to our data. Variant chr18-68684314-T-A is described in ClinVar as [Benign]. Clinvar id is 1241037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMX3	NM_019022.5	c.795-71A>T		intron_variant		ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.795-71A>T		intron_variant		1	NM_019022.5	ENSP00000299608	P1
TMX3	ENST00000564631.5	c.*479-71A>T		intron_variant, NMD_transcript_variant		1		ENSP00000456587
TMX3	ENST00000578765.1	n.370-71A>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3494 AN: 152158 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00321 AC: 4305 AN: 1340692 Hom.: 105 Cov.: 20 AF XY: 0.00288 AC XY: 1942 AN XY: 673274

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.00669

Gnomad4 ASJ exome AF: 0.000726

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000342

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.0230 AC: 3507 AN: 152276 Hom.: 138 Cov.: 32 AF XY: 0.0218 AC XY: 1620 AN XY: 74454

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0192 Hom.: 10

Bravo AF: 0.0262

Asia WGS AF: 0.00608 AC: 21 AN: 3466

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 23, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17079562; hg19: chr18-66351551;