18-68681214-C-T

Variant names:

• chr18-68681214-C-T
• rs309209
• NM_019022.5:c.906-104G>A

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.906-104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,015,442 control chromosomes in the GnomAD database, including 6,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (4028 hom., cov: 33)
  • Exomes 𝑓: 0.023 (2268 hom.)
• Consequence: TMX3 NM_019022.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.450
• 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 18-68681214-C-T is Benign according to our data. Variant chr18-68681214-C-T is described in ClinVar as [Benign]. Clinvar id is 1283002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMX3	NM_019022.5	c.906-104G>A		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.906-104G>A		intron_variant	Intron 13 of 15	1	NM_019022.5	ENSP00000299608.2
TMX3	ENST00000564631.5	n.*590-104G>A		intron_variant	Intron 12 of 14	1		ENSP00000456587.1
TMX3	ENST00000566135.1	n.30+79G>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20171 AN: 152002 Hom.: 4020 Cov.: 33

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.0737

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0232 AC: 20002 AN: 863320 Hom.: 2268 Cov.: 11 AF XY: 0.0220 AC XY: 9334 AN XY: 423640

African (AFR) AF: 0.460 AC: 8794 AN: 19124

American (AMR) AF: 0.0460 AC: 575 AN: 12496

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 162 AN: 14120

East Asian (EAS) AF: 0.00 AC: 0 AN: 27926

South Asian (SAS) AF: 0.00412 AC: 115 AN: 27942

European-Finnish (FIN) AF: 0.00519 AC: 146 AN: 28144

Middle Eastern (MID) AF: 0.0321 AC: 84 AN: 2618

European-Non Finnish (NFE) AF: 0.0123 AC: 8508 AN: 693254

Other (OTH) AF: 0.0429 AC: 1618 AN: 37696

GnomAD4 genome AF: 0.133 AC: 20213 AN: 152122 Hom.: 4028 Cov.: 33 AF XY: 0.128 AC XY: 9494 AN XY: 74400

African (AFR) AF: 0.431 AC: 17867 AN: 41432

American (AMR) AF: 0.0685 AC: 1048 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4834

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10602

Middle Eastern (MID) AF: 0.0828 AC: 24 AN: 290

European-Non Finnish (NFE) AF: 0.0132 AC: 898 AN: 67998

Other (OTH) AF: 0.103 AC: 218 AN: 2116

Alfa AF: 0.0752 Hom.: 654

Bravo AF: 0.152

Asia WGS AF: 0.0290 AC: 103 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.51
DANN	Benign	0.53
PhyloP100		-0.45
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: rs309209; hg19: chr18-66348451;