18-68676761-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_019022.5(TMX3):c.*172C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 766,756 control chromosomes in the GnomAD database, including 519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (99 hom., cov: 32)
  • Exomes 𝑓: 0.034 (420 hom.)
• Consequence: TMX3 NM_019022.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.354

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=-0.85).
• BP6: Variant 18-68676761-G-C is Benign according to our data. Variant chr18-68676761-G-C is described in ClinVar as [Benign]. Clinvar id is 1276356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0263 (3998/152178) while in subpopulation NFE AF= 0.0396 (2693/67988). AF 95% confidence interval is 0.0384. There are 99 homozygotes in gnomad4. There are 1984 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 99 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.*172C>G		3_prime_UTR_variant	16/16	ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.*172C>G		3_prime_UTR_variant	16/16	1	NM_019022.5	P1
TMX3	ENST00000578816.1	n.548C>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3999 AN: 152060 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0161

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0396

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.0339 AC: 20847 AN: 614578 Hom.: 420 Cov.: 8 AF XY: 0.0329 AC XY: 10399 AN XY: 316090

Gnomad4 AFR exome AF: 0.00457

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.0000316

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.0640

Gnomad4 NFE exome AF: 0.0395

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0263 AC: 3998 AN: 152178 Hom.: 99 Cov.: 32 AF XY: 0.0267 AC XY: 1984 AN XY: 74404

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.0396

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0357 Hom.: 13

Bravo AF: 0.0212

Asia WGS AF: 0.00549 AC: 19 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 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	7.0
Dann	Benign	0.54

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: rs117426990; hg19: chr18-66343998;