18-68679813-G-T

Variant names:

• chr18-68679813-G-T
• rs309207
• NM_019022.5:c.1036-282C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_019022.5(TMX3):​c.1036-282C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 151,978 control chromosomes in the GnomAD database, including 9,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (9026 hom., cov: 32)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.07
• Publications: 0 publications found

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-68679813-G-T is Benign according to our data. Variant chr18-68679813-G-T is described in ClinVar as [Benign]. Clinvar id is 1250000.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5	c.1036-282C>A		intron_variant	Intron 14 of 15	ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.1036-282C>A		intron_variant	Intron 14 of 15	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*720-282C>A		intron_variant	Intron 13 of 14	1		ENSP00000456587.1
TMX3	ENST00000566135.1	n.161-282C>A		intron_variant	Intron 2 of 3	3
TMX3	ENST00000578816.1	n.-236C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39878 AN: 151858 Hom.: 8996 Cov.: 32

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0659

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.245

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.263 AC: 39965 AN: 151978 Hom.: 9026 Cov.: 32 AF XY: 0.260 AC XY: 19292 AN XY: 74288

African (AFR) AF: 0.614 AC: 25444 AN: 41416

American (AMR) AF: 0.213 AC: 3248 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 659 AN: 3470

East Asian (EAS) AF: 0.177 AC: 912 AN: 5144

South Asian (SAS) AF: 0.0653 AC: 315 AN: 4824

European-Finnish (FIN) AF: 0.143 AC: 1508 AN: 10562

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.104 AC: 7042 AN: 67990

Other (OTH) AF: 0.245 AC: 518 AN: 2110

Alfa AF: 0.158 Hom.: 4333

Bravo AF: 0.290

Asia WGS AF: 0.189 AC: 659 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.092
DANN	Benign	0.52
PhyloP100		-2.1
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

Other links and lift over

dbSNP: rs309207; hg19: chr18-66347050;