Genetic Variant NM_004618.5:c.*3435C>T (chr17-18271367-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004618.5(TOP3A):c.*3435C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 152,858 control chromosomes in the GnomAD database, including 7,440 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7413 hom., cov: 32)

Exomes 𝑓: 0.22 ( 27 hom. )

Consequence

TOP3A
NM_004618.5 downstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.327

Publications

11 publications found

Variant links:

COSMIC-nc: COSV58175902

Genes affected

TOP3A (HGNC:11992): (DNA topoisomerase III alpha) 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 reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

TOP3A Gene-Disease associations (from GenCC):

microcephaly, growth restriction, and increased sister chromatid exchange 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

TOP3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TOP3A	NM_004618.5 link	c.*3435C>T	downstream_gene_variant	ENST00000321105.10	NP_004609.1	Q13472-1
TOP3A	NM_001320759.2 link	c.*3435C>T	downstream_gene_variant		NP_001307688.1	Q13472-3
TOP3A	XM_047436633.1 link	c.*3435C>T	downstream_gene_variant		XP_047292589.1
TOP3A	XM_047436634.1 link	c.*3435C>T	downstream_gene_variant		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10 link	c.*3435C>T		downstream_gene_variant		1	NM_004618.5	ENSP00000321636.5		Q13472-1
TOP3A	ENST00000493648.1 link	n.*407C>T		downstream_gene_variant		2		ENSP00000465014.1		K7EJ41

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46402

AN:

151934

Hom.:

7412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.346

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.0747

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.293

GnomAD4 exome

AF:

0.216

AC:

174

AN:

806

Hom.:

AF XY:

0.187

AC XY:

AN XY:

454

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.103

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.146

AC:

AN:

198

European-Finnish (FIN)

AF:

0.182

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.272

AC:

123

AN:

452

Other (OTH)

AF:

0.158

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.305

AC:

46439

AN:

152052

Hom.:

7413

Cov.:

AF XY:

0.301

AC XY:

22364

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.346

AC:

14358

AN:

41452

American (AMR)

AF:

0.248

AC:

3791

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

1138

AN:

3472

East Asian (EAS)

AF:

0.0753

AC:

390

AN:

5182

South Asian (SAS)

AF:

0.186

AC:

898

AN:

4818

European-Finnish (FIN)

AF:

0.324

AC:

3423

AN:

10560

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.316

AC:

21455

AN:

67974

Other (OTH)

AF:

0.289

AC:

609

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1606

3211

4817

6422

8028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.305

Hom.:

8801

Bravo

AF:

0.297

Asia WGS

AF:

0.152

AC:

531

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.6

(source)

DANN

Benign

0.62

PhyloP100

0.33

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over