chr20-43973424-A-C

Variant names:

• chr20-43973424-A-C
• rs755427969
• NM_001098797.2:c.157A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001098797.2(TOX2):​c.157A>C​(p.Thr53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T53A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.832
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18798509).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098797.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX2	NM_001098797.2	MANE Select	c.157A>C	p.Thr53Pro	missense	Exon 2 of 9	NP_001092267.1	Q96NM4-4
	TOX2	NM_001098798.2		c.184A>C	p.Thr62Pro	missense	Exon 2 of 8	NP_001092268.1	Q96NM4-1
	TOX2	NM_001098796.2		c.31A>C	p.Thr11Pro	missense	Exon 2 of 9	NP_001092266.1	Q96NM4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOX2	ENST00000341197.9	TSL:2 MANE Select	c.157A>C	p.Thr53Pro	missense	Exon 2 of 9	ENSP00000344724.3	Q96NM4-4
	TOX2	ENST00000372999.5	TSL:1	c.31A>C	p.Thr11Pro	missense	Exon 3 of 10	ENSP00000362090.1	Q96NM4-3
	TOX2	ENST00000864666.1		c.157A>C	p.Thr53Pro	missense	Exon 2 of 10	ENSP00000534725.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.83
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.49
MutPred		0.11		Gain of relative solvent accessibility (P = 0.09)
MVP		0.86
MPC		0.46
ClinPred		0.24	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.25
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs755427969; hg19: chr20-42602064;