rs145256528

Variant names:

• chr22-21957510-G-A
• rs145256528
• NM_001282112.2:c.2193C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001282112.2(TOP3B):​c.2193C>T​(p.Ser731Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (1078 hom., cov: 17)
  • Exomes 𝑓: 0.30 (9968 hom.)
  • Failed GnomAD Quality Control
• Consequence: TOP3B NM_001282112.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.99
• Publications: 4 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 (BayesDel_noAF=-0.85).
• BP6: Variant 22-21957510-G-A is Benign according to our data. Variant chr22-21957510-G-A is described in ClinVar as Benign. ClinVar VariationId is 770011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.

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.2193C>T	p.Ser731Ser	synonymous	Exon 18 of 18	NP_001269041.1	O95985-1
	TOP3B	NM_001282113.2		c.2193C>T	p.Ser731Ser	synonymous	Exon 18 of 18	NP_001269042.1	O95985-1
	TOP3B	NM_001349845.2		c.2193C>T	p.Ser731Ser	synonymous	Exon 19 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.2193C>T	p.Ser731Ser	synonymous	Exon 18 of 18	ENSP00000349705.5	O95985-1
	TOP3B	ENST00000398793.6	TSL:1	c.2193C>T	p.Ser731Ser	synonymous	Exon 18 of 18	ENSP00000381773.2	O95985-1
	PPM1F-AS1	ENST00000458178.2	TSL:1	n.17730G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 30543 AN: 109466 Hom.: 1076 Cov.: 17

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.205 AC: 18064 AN: 87952 AF XY: 0.204

Gnomad AFR exome AF: 0.0949

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.249

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.302 AC: 215523 AN: 714000 Hom.: 9968 Cov.: 12 AF XY: 0.296 AC XY: 107396 AN XY: 362998

African (AFR) AF: 0.0912 AC: 1733 AN: 19000

American (AMR) AF: 0.167 AC: 4815 AN: 28826

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 5019 AN: 17678

East Asian (EAS) AF: 0.298 AC: 5941 AN: 19920

South Asian (SAS) AF: 0.196 AC: 10359 AN: 52792

European-Finnish (FIN) AF: 0.243 AC: 8324 AN: 34282

Middle Eastern (MID) AF: 0.293 AC: 738 AN: 2516

European-Non Finnish (NFE) AF: 0.333 AC: 168941 AN: 506668

Other (OTH) AF: 0.299 AC: 9653 AN: 32318

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.279 AC: 30540 AN: 109556 Hom.: 1078 Cov.: 17 AF XY: 0.278 AC XY: 14549 AN XY: 52326

African (AFR) AF: 0.119 AC: 3596 AN: 30184

American (AMR) AF: 0.284 AC: 3008 AN: 10590

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 919 AN: 2736

East Asian (EAS) AF: 0.346 AC: 1169 AN: 3376

South Asian (SAS) AF: 0.290 AC: 869 AN: 2992

European-Finnish (FIN) AF: 0.377 AC: 2656 AN: 7048

Middle Eastern (MID) AF: 0.335 AC: 87 AN: 260

European-Non Finnish (NFE) AF: 0.350 AC: 17582 AN: 50228

Other (OTH) AF: 0.297 AC: 424 AN: 1430

Alfa AF: 0.259 Hom.: 284

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.58
DANN	Benign	0.86
PhyloP100		-2.0
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: rs145256528; hg19: chr22-22311882; COSMIC: COSV54282814; COSMIC: COSV54282814;