chr20-43914916-G-T

Position:

• chr20-43914916-G-T

Variant summary

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

The NM_001098797.2(TOX2):​c.25G>T​(p.Ala9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000992 in 1,008,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

Genes affected

TOX2 (HGNC:16095): (TOX high mobility group box family member 2) Enables transcription coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [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=0.20272979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOX2	NM_001098797.2	c.25G>T	p.Ala9Ser	missense_variant	1/9	ENST00000341197.9	NP_001092267.1
TOX2	XM_047440563.1	c.25G>T	p.Ala9Ser	missense_variant	1/8		XP_047296519.1
TOX2	XM_047440565.1	c.25G>T	p.Ala9Ser	missense_variant	1/7		XP_047296521.1
TOX2	XM_047440561.1	c.-227G>T		5_prime_UTR_variant	1/10		XP_047296517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOX2	ENST00000341197.9	c.25G>T	p.Ala9Ser	missense_variant	1/9	2	NM_001098797.2	ENSP00000344724	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.92e-7 AC: 1 AN: 1008238 Hom.: 0 Cov.: 30 AF XY: 0.00000208 AC XY: 1 AN XY: 481128

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: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

Jan 04, 2024

The c.25G>T (p.A9S) alteration is located in exon 1 (coding exon 1) of the TOX2 gene. This alteration results from a G to T substitution at nucleotide position 25, causing the alanine (A) at amino acid position 9 to be replaced by a serine (S). 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
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.083
Sift	Benign	0.11	T
Sift4G	Benign	0.47	T
Vest4		0.26
MutPred		0.18		Gain of glycosylation at A9 (P = 0.0187);
MVP		0.12
MPC		0.60
ClinPred		0.74	D
GERP RS		2.3
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs909809329; hg19: chr20-42543556;