18-68681091-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_019022.5(TMX3):c.925G>A(p.Val309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,574,074 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (15 hom.)
• Consequence: TMX3 NM_019022.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008639067).
• BP6: Variant 18-68681091-C-T is Benign according to our data. Variant chr18-68681091-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3040971.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX3	NM_019022.5	c.925G>A	p.Val309Ile	missense_variant	14/16	ENST00000299608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX3	ENST00000299608.7	c.925G>A	p.Val309Ile	missense_variant	14/16	1	NM_019022.5	P1
TMX3	ENST00000564631.5	c.*609G>A		3_prime_UTR_variant, NMD_transcript_variant	13/15	1
TMX3	ENST00000566135.1	n.50G>A		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00207 AC: 468 AN: 225738 Hom.: 2 AF XY: 0.00210 AC XY: 257 AN XY: 122452

Gnomad AFR exome AF: 0.000669

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00233

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00325 AC: 4616 AN: 1421804 Hom.: 15 Cov.: 29 AF XY: 0.00323 AC XY: 2276 AN XY: 705310

Gnomad4 AFR exome AF: 0.000438

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00384

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74466

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00296 Hom.: 2

Bravo AF: 0.00224

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00198 AC: 241

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMX3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	14
Dann	Benign	0.68
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
MutationTaster	Benign	0.84	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.064
Sift	Benign	0.89	T
Sift4G	Benign	0.74	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.34
MPC		0.22
ClinPred		0.011	T
GERP RS		4.9
Varity_R		0.013
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117449369; hg19: chr18-66348328; COSMIC: COSV99076736; COSMIC: COSV99076736;