NM_019022.5:c.906-225A>G

Variant names:

• chr18-68681335-T-C
• rs111324140
• NM_019022.5:c.906-225A>G

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.906-225A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 611,580 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (33 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.411
• 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=-0.7).
• BP6: Variant 18-68681335-T-C is Benign according to our data. Variant chr18-68681335-T-C is described in ClinVar as [Benign]. Clinvar id is 1265855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5	c.906-225A>G		intron_variant	Intron 13 of 15	ENST00000299608.7	NP_061895.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMX3	ENST00000299608.7	c.906-225A>G		intron_variant	Intron 13 of 15	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*590-225A>G		intron_variant	Intron 12 of 14	1		ENSP00000456587.1
TMX3	ENST00000566135.1	n.-13A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3320 AN: 152148 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00210 AC: 966 AN: 459314 Hom.: 33 Cov.: 7 AF XY: 0.00182 AC XY: 404 AN XY: 222568

African (AFR) AF: 0.0806 AC: 819 AN: 10160

American (AMR) AF: 0.00510 AC: 20 AN: 3920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7072

East Asian (EAS) AF: 0.00 AC: 0 AN: 11920

South Asian (SAS) AF: 0.00 AC: 0 AN: 9422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8282

Middle Eastern (MID) AF: 0.000751 AC: 1 AN: 1332

European-Non Finnish (NFE) AF: 0.0000309 AC: 12 AN: 387872

Other (OTH) AF: 0.00590 AC: 114 AN: 19334

GnomAD4 genome AF: 0.0219 AC: 3332 AN: 152266 Hom.: 112 Cov.: 32 AF XY: 0.0211 AC XY: 1571 AN XY: 74454

African (AFR) AF: 0.0757 AC: 3146 AN: 41538

American (AMR) AF: 0.00961 AC: 147 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0263 Hom.: 20

Bravo AF: 0.0252

Asia WGS AF: 0.00694 AC: 24 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.70
CADD	Benign	4.1
DANN	Benign	0.72
PhyloP100		0.41
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: rs111324140; hg19: chr18-66348572;