chr17-18277723-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting
The NM_004618.5(TOP3A):c.2779G>T(p.Glu927*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_004618.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TOP3A | NM_004618.5 | c.2779G>T | p.Glu927* | stop_gained | Exon 18 of 19 | ENST00000321105.10 | NP_004609.1 | |
TOP3A | NM_001320759.2 | c.2494G>T | p.Glu832* | stop_gained | Exon 17 of 18 | NP_001307688.1 | ||
TOP3A | XM_047436633.1 | c.1858G>T | p.Glu620* | stop_gained | Exon 16 of 17 | XP_047292589.1 | ||
TOP3A | XM_047436634.1 | c.1858G>T | p.Glu620* | stop_gained | Exon 16 of 17 | XP_047292590.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000525 AC: 8AN: 152274Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000179 AC: 45AN: 250912Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135610
GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461538Hom.: 0 Cov.: 32 AF XY: 0.0000990 AC XY: 72AN XY: 727016
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152392Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74524
ClinVar
Submissions by phenotype
Microcephaly, growth restriction, and increased sister chromatid exchange 2 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with progressive external ophthalmoplegia with mitochondrial DNA deletions 5 (MIM#618098) and microcephaly, growth restriction, and increased sister chromatid exchange 2 (MIM#618097). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (45 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the loss of part of the GRF-type 2 zinc finger motif (Uniprot, NCBI). (I) 0705 - No comparable protein truncation variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at