rs755462826

Variant names:

• chr17-18277693-C-A
• rs755462826
• NM_004618.5:c.2809G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-18277693-C-A
• chr17-18277693-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004618.5(TOP3A):​c.2809G>T​(p.Asp937Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.2809G>T	p.Asp937Tyr	missense_variant	Exon 18 of 19	ENST00000321105.10	NP_004609.1
TOP3A	NM_001320759.2	c.2524G>T	p.Asp842Tyr	missense_variant	Exon 17 of 18		NP_001307688.1
TOP3A	XM_047436633.1	c.1888G>T	p.Asp630Tyr	missense_variant	Exon 16 of 17		XP_047292589.1
TOP3A	XM_047436634.1	c.1888G>T	p.Asp630Tyr	missense_variant	Exon 16 of 17		XP_047292590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.2809G>T	p.Asp937Tyr	missense_variant	Exon 18 of 19	1	NM_004618.5	ENSP00000321636.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457484 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Benign	0.91
DEOGEN2	Benign	0.34	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Pathogenic	4.1	H;H;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.0	.;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.81		Loss of disorder (P = 0.013);Loss of disorder (P = 0.013);.;
MVP		0.47
MPC		0.82
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs755462826; hg19: chr17-18181007;