17-18277682-G-A

Variant names:

• chr17-18277682-G-A
• rs140837737
• NM_004618.5:c.2820C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004618.5(TOP3A):​c.2820C>T​(p.Thr940Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,605,208 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T940T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (4 hom.)
• Consequence: TOP3A NM_004618.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0270
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-18277682-G-A is Benign according to our data. Variant chr17-18277682-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 916326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00222 (338/152364) while in subpopulation AFR AF = 0.00354 (147/41582). AF 95% confidence interval is 0.00307. There are 0 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.2820C>T	p.Thr940Thr	synonymous	Exon 18 of 19	NP_004609.1	Q13472-1
	TOP3A	NM_001320759.2		c.2535C>T	p.Thr845Thr	synonymous	Exon 17 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.2820C>T	p.Thr940Thr	synonymous	Exon 18 of 19	ENSP00000321636.5	Q13472-1
	TOP3A	ENST00000580095.5	TSL:1	c.2745C>T	p.Thr915Thr	synonymous	Exon 18 of 19	ENSP00000462790.1	Q13472-2
	TOP3A	ENST00000924978.1		c.2976C>T	p.Thr992Thr	synonymous	Exon 19 of 20	ENSP00000595037.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00144 AC: 358 AN: 248778 AF XY: 0.00153

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00500

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00112 AC: 1625 AN: 1452844 Hom.: 4 Cov.: 32 AF XY: 0.00114 AC XY: 825 AN XY: 720632

African (AFR) AF: 0.00475 AC: 158 AN: 33298

American (AMR) AF: 0.00121 AC: 54 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.00396 AC: 103 AN: 26020

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39420

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86126

European-Finnish (FIN) AF: 0.000678 AC: 36 AN: 53108

Middle Eastern (MID) AF: 0.00473 AC: 27 AN: 5710

European-Non Finnish (NFE) AF: 0.00102 AC: 1130 AN: 1104688

Other (OTH) AF: 0.00144 AC: 86 AN: 59908

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74518

African (AFR) AF: 0.00354 AC: 147 AN: 41582

American (AMR) AF: 0.00183 AC: 28 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00220

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.3
DANN	Benign	0.55
PhyloP100		0.027
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140837737; hg19: chr17-18180996;