18-68683027-G-A

Variant names:

• chr18-68683027-G-A
• rs8083026
• NM_019022.5:c.849-46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019022.5(TMX3):​c.849-46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,542,430 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (103 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.565

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 18-68683027-G-A is Benign according to our data. Variant chr18-68683027-G-A is described in ClinVar as [Benign]. Clinvar id is 1281736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5	c.849-46C>T		intron_variant	Intron 12 of 15	ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.849-46C>T		intron_variant	Intron 12 of 15	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*533-46C>T		intron_variant	Intron 11 of 14	1		ENSP00000456587.1
TMX3	ENST00000578765.1	n.424-46C>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3309 AN: 151898 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00555 AC: 1325 AN: 238764 AF XY: 0.00442

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.00371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00219 AC: 3039 AN: 1390412 Hom.: 103 Cov.: 21 AF XY: 0.00184 AC XY: 1280 AN XY: 694752

Gnomad4 AFR exome AF: 0.0797 AC: 2510 AN: 31500

Gnomad4 AMR exome AF: 0.00431 AC: 184 AN: 42684

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25234

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38900

Gnomad4 SAS exome AF: 0.000109 AC: 9 AN: 82226

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52330

Gnomad4 NFE exome AF: 0.0000560 AC: 59 AN: 1054180

Gnomad4 Remaining exome AF: 0.00464 AC: 268 AN: 57762

GnomAD4 genome AF: 0.0218 AC: 3321 AN: 152018 Hom.: 111 Cov.: 32 AF XY: 0.0211 AC XY: 1571 AN XY: 74354

Gnomad4 AFR AF: 0.0756 AC: 0.0756442 AN: 0.0756442

Gnomad4 AMR AF: 0.00962 AC: 0.00962042 AN: 0.00962042

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00125 AC: 0.00124533 AN: 0.00124533

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000736 AC: 0.0000736182 AN: 0.0000736182

Gnomad4 OTH AF: 0.0118 AC: 0.0118483 AN: 0.0118483

Alfa AF: 0.00511 Hom.: 5

Bravo AF: 0.0253

Asia WGS AF: 0.00693 AC: 24 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.8
DANN	Benign	0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs8083026; hg19: chr18-66350264;