rs34147280

Variant names:

• chr17-40392277-A-C
• rs34147280
• NM_001067.4:c.4029T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-40392277-A-C
• chr17-40392277-A-G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001067.4(TOP2A):​c.4029T>G​(p.Thr1343Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,611,588 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: TOP2A NM_001067.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.65
• Publications: 2 publications found

Genes affected

TOP2A (HGNC:11989): (DNA topoisomerase II alpha) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-40392277-A-C is Benign according to our data. Variant chr17-40392277-A-C is described in ClinVar as Benign. ClinVar VariationId is 768879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.65 with no splicing effect.
• BS2: High AC in GnomAd4 at 515 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001067.4. 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
	TOP2A	NM_001067.4	MANE Select	c.4029T>G	p.Thr1343Thr	synonymous	Exon 31 of 35	NP_001058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2A	ENST00000423485.6	TSL:1 MANE Select	c.4029T>G	p.Thr1343Thr	synonymous	Exon 31 of 35	ENSP00000411532.1	P11388-1
	TOP2A	ENST00000917864.1		c.3846T>G	p.Thr1282Thr	synonymous	Exon 30 of 34	ENSP00000587923.1
	TOP2A	ENST00000917865.1		c.3414T>G	p.Thr1138Thr	synonymous	Exon 26 of 30	ENSP00000587924.1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152202 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000897 AC: 219 AN: 244210 AF XY: 0.000619

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000561

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000334 AC: 487 AN: 1459268 Hom.: 3 Cov.: 33 AF XY: 0.000281 AC XY: 204 AN XY: 725720

African (AFR) AF: 0.0121 AC: 406 AN: 33450

American (AMR) AF: 0.000564 AC: 25 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85754

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53296

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110690

Other (OTH) AF: 0.000713 AC: 43 AN: 60282

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152320 Hom.: 4 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74476

African (AFR) AF: 0.0116 AC: 483 AN: 41568

American (AMR) AF: 0.00196 AC: 30 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00383

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.79
PhyloP100		2.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34147280; hg19: chr17-38548529;