22-21957233-G-C

Variant names:

• chr22-21957233-G-C
• rs1270601428
• NM_001282112.2:c.2470C>G

Variant summary

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

The NM_001282112.2(TOP3B):​c.2470C>G​(p.Arg824Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000371 in 1,346,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: TOP3B NM_001282112.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

Genes affected

TOP3B (HGNC:11993): (DNA topoisomerase III beta) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus relaxing the supercoils and altering the topology of DNA. The enzyme interacts with DNA helicase SGS1 and plays a role in DNA recombination, cellular aging and maintenance of genome stability. Low expression of this gene may be related to higher survival rates in breast cancer patients. This gene has a pseudogene on chromosome 22. Alternate splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Aug 2013]

PPM1F-AS1 (HGNC:40888): (PPM1F antisense RNA 1)

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=0.193843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3B	NM_001282112.2	c.2470C>G	p.Arg824Gly	missense_variant	Exon 18 of 18	ENST00000357179.10	NP_001269041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3B	ENST00000357179.10	c.2470C>G	p.Arg824Gly	missense_variant	Exon 18 of 18	1	NM_001282112.2	ENSP00000349705.5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD3 exomes AF: 0.00000872 AC: 1 AN: 114646 Hom.: 0 AF XY: 0.0000162 AC XY: 1 AN XY: 61640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000371 AC: 5 AN: 1346990 Hom.: 0 Cov.: 22 AF XY: 0.00000450 AC XY: 3 AN XY: 666792

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: 0.00000482

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2470C>G (p.R824G) alteration is located in exon 18 (coding exon 17) of the TOP3B gene. This alteration results from a C to G substitution at nucleotide position 2470, causing the arginine (R) at amino acid position 824 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.084
Sift	Uncertain	0.012	D;D
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;B
Vest4		0.45
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);
MVP		0.57
MPC		2.3
ClinPred		0.48	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.52

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: rs1270601428; hg19: chr22-22311605;