18-68691166-G-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+129C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 506,102 control chromosomes in the GnomAD database, including 8,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (5011 hom., cov: 32)
  • Exomes 𝑓: 0.12 (3497 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.465

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=-0.98).
• BP6: Variant 18-68691166-G-T is Benign according to our data. Variant chr18-68691166-G-T is described in ClinVar as [Benign]. Clinvar id is 1274094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.637+129C>A		intron_variant		ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.637+129C>A		intron_variant		1	NM_019022.5	P1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32086 AN: 151688 Hom.: 4996 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.123 AC: 43441 AN: 354294 Hom.: 3497 Cov.: 6 AF XY: 0.122 AC XY: 21734 AN XY: 178734

Gnomad4 AFR exome AF: 0.443

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.0547

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.0984

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.212 AC: 32146 AN: 151808 Hom.: 5011 Cov.: 32 AF XY: 0.211 AC XY: 15630 AN XY: 74176

Gnomad4 AFR AF: 0.440

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.210

Alfa AF: 0.137 Hom.: 1963

Bravo AF: 0.232

Asia WGS AF: 0.156 AC: 546 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

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	1.2
Dann	Benign	0.67

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: rs309228; hg19: chr18-66358403; COSMIC: COSV55185855; COSMIC: COSV55185855;