22-21975375-G-T

Variant names:

• chr22-21975375-G-T
• rs732466
• NM_001282112.2:c.70+265C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003935.5(TOP3B):​c.70+265C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 364,850 control chromosomes in the GnomAD database, including 2,076 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (863 hom., cov: 32)
  • Exomes 𝑓: 0.10 (1213 hom.)
• Consequence: TOP3B NM_003935.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003935.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3B	NM_001282112.2	MANE Select	c.70+265C>A		intron	N/A	NP_001269041.1
	TOP3B	NM_001282113.2		c.70+265C>A		intron	N/A	NP_001269042.1
	TOP3B	NM_001349845.2		c.70+265C>A		intron	N/A	NP_001336774.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3B	ENST00000357179.10	TSL:1 MANE Select	c.70+265C>A		intron	N/A	ENSP00000349705.5
	TOP3B	ENST00000398793.6	TSL:1	c.70+265C>A		intron	N/A	ENSP00000381773.2
	PPM1F-AS1	ENST00000458178.2	TSL:1	n.35595G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15738 AN: 151938 Hom.: 862 Cov.: 32

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0740

Gnomad SAS AF: 0.0494

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.103 AC: 21992 AN: 212794 Hom.: 1213 Cov.: 4 AF XY: 0.103 AC XY: 11397 AN XY: 110742

African (AFR) AF: 0.0697 AC: 456 AN: 6546

American (AMR) AF: 0.0917 AC: 802 AN: 8742

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 778 AN: 7116

East Asian (EAS) AF: 0.0673 AC: 1073 AN: 15954

South Asian (SAS) AF: 0.0523 AC: 855 AN: 16354

European-Finnish (FIN) AF: 0.116 AC: 1603 AN: 13848

Middle Eastern (MID) AF: 0.121 AC: 120 AN: 994

European-Non Finnish (NFE) AF: 0.115 AC: 14923 AN: 130152

Other (OTH) AF: 0.106 AC: 1382 AN: 13088

GnomAD4 genome AF: 0.104 AC: 15745 AN: 152056 Hom.: 863 Cov.: 32 AF XY: 0.103 AC XY: 7627 AN XY: 74328

African (AFR) AF: 0.0759 AC: 3149 AN: 41488

American (AMR) AF: 0.118 AC: 1800 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3466

East Asian (EAS) AF: 0.0739 AC: 383 AN: 5180

South Asian (SAS) AF: 0.0495 AC: 238 AN: 4810

European-Finnish (FIN) AF: 0.122 AC: 1286 AN: 10576

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8126 AN: 67954

Other (OTH) AF: 0.106 AC: 224 AN: 2104

Alfa AF: 0.109 Hom.: 503

Bravo AF: 0.101

Asia WGS AF: 0.0760 AC: 265 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs732466; hg19: chr22-22329747;