18-68680890-T-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.1035+91A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,307,280 control chromosomes in the GnomAD database, including 1,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.060 (850 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (638 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

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=-0.88).
• BP6: Variant 18-68680890-T-G is Benign according to our data. Variant chr18-68680890-T-G is described in ClinVar as [Benign]. Clinvar id is 1262037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.1035+91A>C		intron_variant		ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.1035+91A>C		intron_variant		1	NM_019022.5	P1
TMX3	ENST00000564631.5	c.*719+91A>C		intron_variant, NMD_transcript_variant		1
TMX3	ENST00000566135.1	n.160+91A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9121 AN: 152108 Hom.: 843 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: 0.000620

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.00733 AC: 8469 AN: 1155054 Hom.: 638 AF XY: 0.00674 AC XY: 3818 AN XY: 566804

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.00820

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000618

Gnomad4 FIN exome AF: 0.0000509

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0601 AC: 9142 AN: 152226 Hom.: 850 Cov.: 32 AF XY: 0.0587 AC XY: 4370 AN XY: 74442

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0366

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.0526

Alfa AF: 0.0102 Hom.: 154

Bravo AF: 0.0697

Asia WGS AF: 0.0100 AC: 36 AN: 3478

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	5.3
Dann	Benign	0.73

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: rs309208; hg19: chr18-66348127;