chr20-7987325-A-T

Position:

• chr20-7987325-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021156.4(TMX4):​c.578T>A​(p.Val193Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMX4 NM_021156.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32128072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMX4	NM_021156.4	c.578T>A	p.Val193Asp	missense_variant	6/8	ENST00000246024.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMX4	ENST00000246024.7	c.578T>A	p.Val193Asp	missense_variant	6/8	1	NM_021156.4	P1
TMX4	ENST00000527925.1	c.494T>A	p.Val165Asp	missense_variant	5/6	5
TMX4	ENST00000530935.1	n.565T>A		non_coding_transcript_exon_variant	6/6	4
TMX4	ENST00000462384.6	c.*585T>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.578T>A (p.V193D) alteration is located in exon 6 (coding exon 6) of the TMX4 gene. This alteration results from a T to A substitution at nucleotide position 578, causing the valine (V) at amino acid position 193 to be replaced by an aspartic acid (D). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.016	D;.
Polyphen		0.89	P;.
Vest4		0.77
MutPred		0.56		Loss of stability (P = 0.1324);.;
MVP		0.53
MPC		0.38
ClinPred		0.93	D
GERP RS		6.2
Varity_R		0.58
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-7967972;