chr17-40416427-A-C

Variant names:

• chr17-40416427-A-C
• rs796052143
• NM_001067.4:c.263T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001067.4(TOP2A):​c.263T>G​(p.Ile88Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,577,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I88T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TOP2A NM_001067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.78
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP2A	NM_001067.4	c.263T>G	p.Ile88Ser	missense_variant	Exon 3 of 35	ENST00000423485.6	NP_001058.2
TOP2A	XM_005257632.2	c.227T>G	p.Ile76Ser	missense_variant	Exon 3 of 35		XP_005257689.1
TOP2A	XM_011525165.3	c.263T>G	p.Ile88Ser	missense_variant	Exon 3 of 32		XP_011523467.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP2A	ENST00000423485.6	c.263T>G	p.Ile88Ser	missense_variant	Exon 3 of 35	1	NM_001067.4	ENSP00000411532.1
TOP2A	ENST00000581055.1	c.227T>G	p.Ile76Ser	missense_variant	Exon 3 of 5	4		ENSP00000462908.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425380 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 707976

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32656

American (AMR) AF: 0.00 AC: 0 AN: 41196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25568

East Asian (EAS) AF: 0.00 AC: 0 AN: 38962

South Asian (SAS) AF: 0.00 AC: 0 AN: 82366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087528

Other (OTH) AF: 0.00 AC: 0 AN: 59136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.77		Loss of stability (P = 0.0116);.;
MVP		0.86
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.96

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: rs796052143; hg19: chr17-38572679;