rs75602167

chr22-21963982-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 33)
  • Exomes 𝑓: 0.017 (325 hom.)
• Consequence: TOP3B NM_001282112.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.32

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 Benign. Variant got -14 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 id is 3060731.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP3B	NM_001282112.2	c.1145A>G	p.His382Arg	missense_variant	11/18	ENST00000357179.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP3B	ENST00000357179.10	c.1145A>G	p.His382Arg	missense_variant	11/18	1	NM_001282112.2	P1
PPM1F-AS1	ENST00000458178.2	n.24202T>C		non_coding_transcript_exon_variant	2/2	1

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

GnomAD3 exomes AF: 0.0141 AC: 3508 AN: 249470 Hom.: 56 AF XY: 0.0140 AC XY: 1896 AN XY: 134970

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 SAS exome AF: 0.00243

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

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00258

Gnomad4 FIN exome AF: 0.00522

Gnomad4 NFE exome AF: 0.0184

Gnomad4 OTH exome AF: 0.0203

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

Gnomad4 AFR AF: 0.00317

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00329

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0196 Hom.: 23

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TOP3B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.060
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.76	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.048
Sift	Benign	0.57	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.11	B;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

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: rs75602167; hg19: chr22-22318354;