17-40406827-C-T

Variant names:

• chr17-40406827-C-T
• rs140672916
• NM_001067.4:c.1737+5G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001067.4(TOP2A):​c.1737+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,595,584 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (29 hom.)
• Consequence: TOP2A NM_001067.4 splice_region, intron
• Scores: Splicing: ADA: 0.1813
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.434
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-40406827-C-T is Benign according to our data. Variant chr17-40406827-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587549.
• BS2: High AC in GnomAd4 at 555 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2A	NM_001067.4	MANE Select	c.1737+5G>A		splice_region intron	N/A	NP_001058.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP2A	ENST00000423485.6	TSL:1 MANE Select	c.1737+5G>A		splice_region intron	N/A	ENSP00000411532.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00582

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00409 AC: 945 AN: 230946 AF XY: 0.00441

Gnomad AFR exome AF: 0.000835

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000934

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00332

Gnomad NFE exome AF: 0.00614

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00496 AC: 7153 AN: 1443366 Hom.: 29 Cov.: 30 AF XY: 0.00508 AC XY: 3644 AN XY: 717686

African (AFR) AF: 0.000602 AC: 20 AN: 33196

American (AMR) AF: 0.00179 AC: 76 AN: 42520

Ashkenazi Jewish (ASJ) AF: 0.000697 AC: 18 AN: 25834

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39522

South Asian (SAS) AF: 0.00436 AC: 371 AN: 85126

European-Finnish (FIN) AF: 0.00402 AC: 213 AN: 52968

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5744

European-Non Finnish (NFE) AF: 0.00563 AC: 6190 AN: 1098660

Other (OTH) AF: 0.00403 AC: 241 AN: 59796

GnomAD4 genome AF: 0.00365 AC: 555 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74432

African (AFR) AF: 0.000915 AC: 38 AN: 41534

American (AMR) AF: 0.00354 AC: 54 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4818

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00582 AC: 396 AN: 68006

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00446 Hom.: 9

Bravo AF: 0.00322

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	TOP2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.49
DANN	Benign	0.49
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.16
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: rs140672916; hg19: chr17-38563079;