chr14-21492761-C-A

Variant names:

• chr14-21492761-C-A
• NM_014828.4:c.1145C>A

Variant summary

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

The NM_014828.4(TOX4):​c.1145C>A​(p.Ser382Tyr) 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)
• Consequence: TOX4 NM_014828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOX4	NM_014828.4	c.1145C>A	p.Ser382Tyr	missense_variant	Exon 7 of 9	ENST00000448790.7	NP_055643.1
TOX4	NM_001303523.2	c.1076C>A	p.Ser359Tyr	missense_variant	Exon 6 of 8		NP_001290452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOX4	ENST00000448790.7	c.1145C>A	p.Ser382Tyr	missense_variant	Exon 7 of 9	1	NM_014828.4	ENSP00000393080.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 67

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1145C>A (p.S382Y) alteration is located in exon 7 (coding exon 7) of the TOX4 gene. This alteration results from a C to A substitution at nucleotide position 1145, causing the serine (S) at amino acid position 382 to be replaced by a tyrosine (Y). 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	0.60
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;T
M_CAP	Benign	0.0023	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.70	T
REVEL	Benign	0.24
Sift4G	Uncertain	0.036	D;D
Polyphen		0.99	D;D
Vest4		0.78
MutPred		0.46		Gain of catalytic residue at Q383 (P = 7e-04);Gain of catalytic residue at Q383 (P = 7e-04);
MVP		0.36
ClinPred		0.86	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.68

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.

Other links and lift over

hg19: chr14-21960920;