NM_004618.5:c.*3435C>T

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

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.327

Publications

11 publications found
Variant links:
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)

Genome browser will be placed here

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 HGVSp Effect Exon rank MANE Protein UniProt
TOP3ANM_004618.5 linkc.*3435C>T downstream_gene_variant ENST00000321105.10 NP_004609.1 Q13472-1
TOP3ANM_001320759.2 linkc.*3435C>T downstream_gene_variant NP_001307688.1 Q13472-3
TOP3AXM_047436633.1 linkc.*3435C>T downstream_gene_variant XP_047292589.1
TOP3AXM_047436634.1 linkc.*3435C>T downstream_gene_variant XP_047292590.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TOP3AENST00000321105.10 linkc.*3435C>T downstream_gene_variant 1 NM_004618.5 ENSP00000321636.5 Q13472-1
TOP3AENST00000493648.1 linkn.*407C>T downstream_gene_variant 2 ENSP00000465014.1 K7EJ41

Frequencies

GnomAD3 genomes
AF:
0.305
AC:
46402
AN:
151934
Hom.:
7412
Cov.:
32
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.:
27
AF XY:
0.187
AC XY:
85
AN XY:
454
show subpopulations
African (AFR)
AC:
0
AN:
0
American (AMR)
AF:
0.103
AC:
6
AN:
58
Ashkenazi Jewish (ASJ)
AF:
0.333
AC:
2
AN:
6
East Asian (EAS)
AF:
0.00
AC:
0
AN:
6
South Asian (SAS)
AF:
0.146
AC:
29
AN:
198
European-Finnish (FIN)
AF:
0.182
AC:
8
AN:
44
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4
European-Non Finnish (NFE)
AF:
0.272
AC:
123
AN:
452
Other (OTH)
AF:
0.158
AC:
6
AN:
38
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
8
15
23
30
38
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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.:
32
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:
87
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
0
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
0
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
DANN
Benign
0.62
PhyloP100
0.33

Splicing

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

Publications

Other links and lift over

dbSNP: rs12945597; hg19: chr17-18174681; COSMIC: COSV58175902; API