20-44006767-A-G

Position:

• chr20-44006767-A-G

Variant summary

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

The NM_001098797.2(TOX2):​c.386A>G​(p.His129Arg) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: TOX2 NM_001098797.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.92

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOX2	NM_001098797.2	c.386A>G	p.His129Arg	missense_variant	3/9	ENST00000341197.9	NP_001092267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOX2	ENST00000341197.9	c.386A>G	p.His129Arg	missense_variant	3/9	2	NM_001098797.2	ENSP00000344724	P4
TOX2	ENST00000372999.5	c.260A>G	p.His87Arg	missense_variant	4/10	1		ENSP00000362090	A1
TOX2	ENST00000358131.5	c.413A>G	p.His138Arg	missense_variant	3/8	2		ENSP00000350849
TOX2	ENST00000423191.6	c.260A>G	p.His87Arg	missense_variant	3/9	2		ENSP00000390278	A1

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

Feb 10, 2022

The c.386A>G (p.H129R) alteration is located in exon 3 (coding exon 3) of the TOX2 gene. This alteration results from a A to G substitution at nucleotide position 386, causing the histidine (H) at amino acid position 129 to be replaced by an arginine (R). 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	0.26
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	.;.;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	2.0	.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.98	.;.;.;D
Vest4		0.83
MutPred		0.23		.;.;.;Loss of catalytic residue at L140 (P = 0.039);
MVP		0.68
MPC		1.1
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.64

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: chr20-42635407;