18-68681226-T-C

Variant names:

• chr18-68681226-T-C
• rs309210
• NM_019022.5:c.906-116A>G

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.906-116A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 924,920 control chromosomes in the GnomAD database, including 5,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (4018 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1898 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.242
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 18-68681226-T-C is Benign according to our data. Variant chr18-68681226-T-C is described in ClinVar as Benign. ClinVar VariationId is 1247350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019022.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	NM_019022.5	MANE Select	c.906-116A>G		intron	N/A	NP_061895.3
	TMX3	NM_001350514.2		c.825-116A>G		intron	N/A	NP_001337443.1
	TMX3	NM_001350515.2		c.483-116A>G		intron	N/A	NP_001337444.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMX3	ENST00000299608.7	TSL:1 MANE Select	c.906-116A>G		intron	N/A	ENSP00000299608.2	Q96JJ7-1
	TMX3	ENST00000564631.5	TSL:1	n.*590-116A>G		intron	N/A	ENSP00000456587.1	H3BVI1
	TMX3	ENST00000915516.1		c.1029-116A>G		intron	N/A	ENSP00000585575.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20160 AN: 152094 Hom.: 4010 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0687

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0216 AC: 16673 AN: 772708 Hom.: 1898 Cov.: 10 AF XY: 0.0205 AC XY: 7768 AN XY: 379394

African (AFR) AF: 0.448 AC: 7320 AN: 16322

American (AMR) AF: 0.0464 AC: 473 AN: 10204

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 139 AN: 13186

East Asian (EAS) AF: 0.0000380 AC: 1 AN: 26294

South Asian (SAS) AF: 0.00322 AC: 74 AN: 22960

European-Finnish (FIN) AF: 0.00512 AC: 134 AN: 26158

Middle Eastern (MID) AF: 0.0301 AC: 72 AN: 2392

European-Non Finnish (NFE) AF: 0.0113 AC: 7019 AN: 620858

Other (OTH) AF: 0.0420 AC: 1441 AN: 34334

GnomAD4 genome AF: 0.133 AC: 20202 AN: 152212 Hom.: 4018 Cov.: 32 AF XY: 0.127 AC XY: 9490 AN XY: 74458

African (AFR) AF: 0.431 AC: 17856 AN: 41462

American (AMR) AF: 0.0685 AC: 1048 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4826

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10624

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0132 AC: 898 AN: 68030

Other (OTH) AF: 0.103 AC: 218 AN: 2114

Alfa AF: 0.0426 Hom.: 149

Bravo AF: 0.152

Asia WGS AF: 0.0290 AC: 103 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.40
PhyloP100		-0.24
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: rs309210; hg19: chr18-66348463;