rs117449369

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019022.5(TMX3):​c.925G>T​(p.Val309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,421,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TMX3
NM_019022.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12782001).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMX3NM_019022.5 linkc.925G>T p.Val309Leu missense_variant Exon 14 of 16 ENST00000299608.7 NP_061895.3 Q96JJ7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMX3ENST00000299608.7 linkc.925G>T p.Val309Leu missense_variant Exon 14 of 16 1 NM_019022.5 ENSP00000299608.2 Q96JJ7-1
TMX3ENST00000564631.5 linkn.*609G>T non_coding_transcript_exon_variant Exon 13 of 15 1 ENSP00000456587.1 H3BVI1
TMX3ENST00000564631.5 linkn.*609G>T 3_prime_UTR_variant Exon 13 of 15 1 ENSP00000456587.1 H3BVI1
TMX3ENST00000566135.1 linkn.50G>T non_coding_transcript_exon_variant Exon 2 of 4 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.03e-7
AC:
1
AN:
1421862
Hom.:
0
Cov.:
29
AF XY:
0.00000142
AC XY:
1
AN XY:
705338
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.13e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Benign
0.0054
T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.061
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
0.53
N
REVEL
Benign
0.048
Sift
Benign
1.0
T
Sift4G
Benign
0.56
T
Polyphen
0.019
B
Vest4
0.31
MutPred
0.47
Loss of catalytic residue at V309 (P = 0.0658);
MVP
0.36
MPC
0.27
ClinPred
0.74
D
GERP RS
4.9
Varity_R
0.024
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-66348328; API