NM_001282112.2:c.1145A>G

Variant names:

• chr22-21963982-T-C
• rs75602167
• NM_001282112.2:c.1145A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001282112.2(TOP3B):​c.1145A>G​(p.His382Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,612,800 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 33)
  • Exomes 𝑓: 0.017 (325 hom.)
• Consequence: TOP3B NM_001282112.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.32
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005235821).
• BP6: Variant 22-21963982-T-C is Benign according to our data. Variant chr22-21963982-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060731.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1977/152306) while in subpopulation NFE AF = 0.0179 (1215/68000). AF 95% confidence interval is 0.017. There are 26 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282112.2. 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
	TOP3B	NM_001282112.2	MANE Select	c.1145A>G	p.His382Arg	missense	Exon 11 of 18	NP_001269041.1	O95985-1
	TOP3B	NM_001282113.2		c.1145A>G	p.His382Arg	missense	Exon 11 of 18	NP_001269042.1	O95985-1
	TOP3B	NM_001349845.2		c.1145A>G	p.His382Arg	missense	Exon 12 of 19	NP_001336774.1	O95985-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3B	ENST00000357179.10	TSL:1 MANE Select	c.1145A>G	p.His382Arg	missense	Exon 11 of 18	ENSP00000349705.5	O95985-1
	TOP3B	ENST00000398793.6	TSL:1	c.1145A>G	p.His382Arg	missense	Exon 11 of 18	ENSP00000381773.2	O95985-1
	PPM1F-AS1	ENST00000458178.2	TSL:1	n.24202T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1977 AN: 152188 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0141 AC: 3508 AN: 249470 AF XY: 0.0140

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00433

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0169 AC: 24718 AN: 1460494 Hom.: 325 Cov.: 31 AF XY: 0.0164 AC XY: 11943 AN XY: 726574

African (AFR) AF: 0.00227 AC: 76 AN: 33476

American (AMR) AF: 0.0127 AC: 567 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 1836 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00258 AC: 222 AN: 86122

European-Finnish (FIN) AF: 0.00522 AC: 276 AN: 52854

Middle Eastern (MID) AF: 0.00799 AC: 46 AN: 5754

European-Non Finnish (NFE) AF: 0.0184 AC: 20469 AN: 1111626

Other (OTH) AF: 0.0203 AC: 1226 AN: 60344

GnomAD4 genome AF: 0.0130 AC: 1977 AN: 152306 Hom.: 26 Cov.: 33 AF XY: 0.0122 AC XY: 907 AN XY: 74478

African (AFR) AF: 0.00317 AC: 132 AN: 41586

American (AMR) AF: 0.0157 AC: 240 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1215 AN: 68000

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.0183 Hom.: 31

Bravo AF: 0.0143

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0184 AC: 71

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0207 AC: 178

ExAC AF: 0.0134 AC: 1621

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0209

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TOP3B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.086	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.048
Sift	Benign	0.57	T
Sift4G	Benign	0.63	T
Polyphen		0.11	B
Vest4		0.21
MPC		0.59
ClinPred		0.017	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.48
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75602167; hg19: chr22-22318354;