NM_004618.5:c.2880G>T

Variant names:

• chr17-18274928-C-A
• rs541672157
• NM_004618.5:c.2880G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004618.5(TOP3A):​c.2880G>T​(p.Ser960Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S960S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TOP3A NM_004618.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.908
• Publications: 1 publications found

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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-0.908 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004618.5. 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
	TOP3A	NM_004618.5	MANE Select	c.2880G>T	p.Ser960Ser	synonymous	Exon 19 of 19	NP_004609.1	Q13472-1
	TOP3A	NM_001320759.2		c.2595G>T	p.Ser865Ser	synonymous	Exon 18 of 18	NP_001307688.1	Q13472-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP3A	ENST00000321105.10	TSL:1 MANE Select	c.2880G>T	p.Ser960Ser	synonymous	Exon 19 of 19	ENSP00000321636.5	Q13472-1
	TOP3A	ENST00000580095.5	TSL:1	c.2805G>T	p.Ser935Ser	synonymous	Exon 19 of 19	ENSP00000462790.1	Q13472-2
	TOP3A	ENST00000924978.1		c.3036G>T	p.Ser1012Ser	synonymous	Exon 20 of 20	ENSP00000595037.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

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: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.27
DANN	Benign	0.41
PhyloP100		-0.91
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs541672157; hg19: chr17-18178242;