NM_001067.4:c.4010C>T

Variant names:

• chr17-40392296-G-A
• rs778291076
• NM_001067.4:c.4010C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001067.4(TOP2A):​c.4010C>T​(p.Ser1337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,606,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: TOP2A NM_001067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24538207).
• BS2: High AC in GnomAdExome4 at 44 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.4010C>T	p.Ser1337Leu	missense	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.4010C>T	p.Ser1337Leu	missense	Exon 31 of 35	ENSP00000411532.1	P11388-1
	TOP2A	ENST00000917864.1		c.3827C>T	p.Ser1276Leu	missense	Exon 30 of 34	ENSP00000587923.1
	TOP2A	ENST00000917865.1		c.3395C>T	p.Ser1132Leu	missense	Exon 26 of 30	ENSP00000587924.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000342 AC: 8 AN: 233948 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.0000670

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000303 AC: 44 AN: 1454076 Hom.: 0 Cov.: 32 AF XY: 0.0000221 AC XY: 16 AN XY: 722634

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85112

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1107770

Other (OTH) AF: 0.0000333 AC: 2 AN: 60146

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000663 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Polyphen		0.44	B
Vest4		0.51
MVP		0.31
MPC		0.13
ClinPred		0.16	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.13
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs778291076; hg19: chr17-38548548;