17-18277661-C-A

Variant names:

• chr17-18277661-C-A
• rs769180100
• NM_004618.5:c.2827+14G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004618.5(TOP3A):​c.2827+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TOP3A NM_004618.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0740
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.2827+14G>T		intron	N/A	NP_004609.1	Q13472-1
	TOP3A	NM_001320759.2		c.2542+14G>T		intron	N/A	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.2827+14G>T		intron	N/A	ENSP00000321636.5	Q13472-1
	TOP3A	ENST00000580095.5	TSL:1	c.2752+14G>T		intron	N/A	ENSP00000462790.1	Q13472-2
	TOP3A	ENST00000924978.1		c.2983+14G>T		intron	N/A	ENSP00000595037.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440666 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712348

⚠️ 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: 33140

American (AMR) AF: 0.0000227 AC: 1 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25508

East Asian (EAS) AF: 0.00 AC: 0 AN: 39192

South Asian (SAS) AF: 0.00 AC: 0 AN: 85342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1095964

Other (OTH) AF: 0.00 AC: 0 AN: 59314

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.75
PhyloP100		-0.074
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs769180100; hg19: chr17-18180975;