14-21493058-G-T

Position:

• chr14-21493058-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_014828.4(TOX4):​c.1442G>T​(p.Arg481Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TOX4 NM_014828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53

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]

TOX4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Asymmetric dimethylarginine (size 0) in uniprot entity TOX4_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOX4	NM_014828.4	c.1442G>T	p.Arg481Leu	missense_variant	7/9	ENST00000448790.7	NP_055643.1
TOX4	NM_001303523.2	c.1373G>T	p.Arg458Leu	missense_variant	6/8		NP_001290452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOX4	ENST00000448790.7	c.1442G>T	p.Arg481Leu	missense_variant	7/9	1	NM_014828.4	ENSP00000393080.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727216

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

May 14, 2024

The c.1442G>T (p.R481L) alteration is located in exon 7 (coding exon 7) of the TOX4 gene. This alteration results from a G to T substitution at nucleotide position 1442, causing the arginine (R) at amino acid position 481 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	0.31
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.0026	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.55	T
REVEL	Benign	0.18
Sift4G	Benign	0.25	T;T
Polyphen		0.98	D;D
Vest4		0.66
MutPred		0.45		Gain of catalytic residue at P476 (P = 0.0042);Gain of catalytic residue at P476 (P = 0.0042);
MVP		0.24
ClinPred		0.70	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs115095768; hg19: chr14-21961217;