Variant chr20-7982554-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021156.4(TMX4):c.747T>A(p.Asp249Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMX4
NM_021156.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.728

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023824126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX4	NM_021156.4 linkuse as main transcript	c.747T>A	p.Asp249Glu	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.747T>A	p.Asp249Glu	missense_variant	8/8	1	NM_021156.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Sep 22, 2023

The c.747T>A (p.D249E) alteration is located in exon 8 (coding exon 8) of the TMX4 gene. This alteration results from a T to A substitution at nucleotide position 747, causing the aspartic acid (D) at amino acid position 249 to be replaced by a glutamic acid (E). 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

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0079

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.57

M_CAP

Benign

0.0036

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.68

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.22

REVEL

Benign

0.063

Sift

Benign

0.24

Sift4G

Benign

0.93

Polyphen

0.0030

Vest4

0.067

MutPred

0.13

Loss of loop (P = 0.1242);

MVP

0.16

MPC

0.16

ClinPred

0.14

GERP RS

-5.8

Varity_R

0.037

gMVP

0.060

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over