14-21488846-G-T

Position:

• chr14-21488846-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014828.4(TOX4):​c.575G>T​(p.Arg192Leu) 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: TOX4 NM_014828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.68

Genes affected

TOX4 (HGNC:20161): (TOX high mobility group box family member 4) Predicted to enable chromatin DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in chromatin. Part of PTW/PP1 phosphatase complex. Colocalizes with chromosome, telomeric region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.23855752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOX4	NM_014828.4	c.575G>T	p.Arg192Leu	missense_variant	4/9	ENST00000448790.7	NP_055643.1
TOX4	NM_001303523.2	c.506G>T	p.Arg169Leu	missense_variant	3/8		NP_001290452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOX4	ENST00000448790.7	c.575G>T	p.Arg192Leu	missense_variant	4/9	1	NM_014828.4	ENSP00000393080.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Apr 23, 2024

The c.575G>T (p.R192L) alteration is located in exon 4 (coding exon 4) of the TOX4 gene. This alteration results from a G to T substitution at nucleotide position 575, causing the arginine (R) at amino acid position 192 to be replaced by a leucine (L). 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	0.23
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	.;T;T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;D;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	.;L;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.023	D;.;D;D
Sift4G	Uncertain	0.028	D;T;T;D
Polyphen		0.91	.;P;P;.
Vest4		0.31, 0.31
MutPred		0.36		.;Loss of MoRF binding (P = 0.0441);Loss of MoRF binding (P = 0.0441);.;
MVP		0.16
ClinPred		0.92	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21957005;