Variant 20-7982574-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021156.4(TMX4):c.727G>A(p.Asp243Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

TMX4
NM_021156.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

TMX4 (HGNC:25237): (thioredoxin related transmembrane protein 4) 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 encoded protein has an N-terminal ER-signal sequence, a catalytically active thioredoxin domain, one transmembrane domain and C-terminal ASP/GLU-rich calcium binding domain. Unlike most members of this gene family, it lacks a C-terminal ER-retention sequence. The encoded protein has been shown to have reductase activity in vitro. [provided by RefSeq, Jan 2017]

TMX4 links:

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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=0.10333535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX4	NM_021156.4 linkuse as main transcript	c.727G>A	p.Asp243Asn	missense_variant	8/8	ENST00000246024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX4	ENST00000246024.7 linkuse as main transcript	c.727G>A	p.Asp243Asn	missense_variant	8/8	1	NM_021156.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000726

AC:

AN:

248048

Hom.:

AF XY:

0.0000745

AC XY:

AN XY:

134250

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000787

AC:

115

AN:

1461438

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000944

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The c.727G>A (p.D243N) alteration is located in exon 8 (coding exon 8) of the TMX4 gene. This alteration results from a G to A substitution at nucleotide position 727, causing the aspartic acid (D) at amino acid position 243 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

M_CAP

Benign

0.0042

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.83

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

REVEL

Benign

0.072

Sift

Benign

0.15

Sift4G

Benign

0.32

Polyphen

0.12

Vest4

0.18

MVP

0.47

MPC

0.56

ClinPred

0.12

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.055

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over