This variant has been observed in population databases at an allele frequency exceeding the BA1 threshold: gnomAD v2.1 grpmax FAF 1.056% (Ashkenazi Jewish AF 1.32%, 10 homozygotes) and gnomAD v4.1 grpmax FAF 1.147% (Ashkenazi Jewish AF 1.39%, 102 homozygotes). This frequency and the presence of homozygotes is incompatible with a highly penetrant dominant disorder. BA1 (stand-alone benign) is met.1 This variant is present in gnomAD at an allele frequency exceeding the BS1 threshold: gnomAD v2.1 overall AF 0.76% and gnomAD v4.1 overall AF 0.99%, both well above 0.3%. BS1 (strong benign) is met.2 SpliceAI predicts no significant splice impact for this intronic variant (max delta score 0.07). No in silico evidence supports a deleterious effect. BP4 (supporting benign) is met.3 This variant has been reported in ClinVar as Benign by a clinical laboratory (SCV002760434, Center for Genomic Medicine, Rigshospitalet) with criteria provided. BP6 (supporting benign) is met.4 No pathogenic criteria are met. The variant is an intronic substitution (c.424-28A>G) with no splice impact, absent from COSMIC, and has no functional or segregation data supporting pathogenicity.5
CDC73
Final classification
Benign
CDC73 c.424-28A>G · p.?
CDC73
This variant has been observed in population databases at an allele frequency exceeding the BA1 threshold: gnomAD v2.1 grpmax FAF 1.056% (Ashkenazi Jewish AF 1.32%, 10 homozygotes) and gnomAD v4.1 grpmax FAF 1.147% (Ashkenazi Jewish AF 1.39%, 102 homozygotes). This frequency and the presence of homozygotes is incompatible with a highly penetrant dominant disorder. BA1 (stand-alone benign) is met.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign, BP6 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP4BP6
Benign
CDC73 c.424-28A>G
BA1 + BS1 + BP4 + BP6
→
Benign
Gene diagram
· NM_024529.5 · variants mapped to exon structure
CDC73
NM_024529.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BA1
stand-alone
Benign
This variant has a maximum population allele frequency exceeding 1%. gnomAD v2.1 grpmax FAF is 1.056% (Ashkenazi Jewish AF=1.32%) and gnomAD v4.1 grpmax FAF is 1.147% (Ashkenazi Jewish AF=1.39%). Additionally, 10 homozygotes are observed in gnomAD v2.1 and 102 homozygotes in gnomAD v4.1, incompatible with a highly penetrant dominant disorder.
gnomAD v2.1 grpmax FAF=1.056%Ashkenazi Jewish AF=1.32%10 homozygotes
✓
BS1
strong
Benign
This variant is present in gnomAD at an allele frequency well above 0.3%. gnomAD v2.1 overall AF is 0.76% (2161/282588 alleles) and gnomAD v4.1 overall AF is 0.99% (15162/1526634 alleles), both exceeding the BS1 threshold.
gnomAD v2.1 total AF=0.76% (>0.3%)gnomAD v4.1 total AF=0.99% (>0.3%).
✓
BP4
supporting
Benign
SpliceAI predicts no significant splice impact (max delta score = 0.07). Multiple lines of in silico evidence (absence of splice-altering prediction, no REVEL/BayesDel scores for intronic variant) support a benign interpretation.
SpliceAI max delta 0.07no evidence of deleterious splicing effect.
✓
BP6
supporting
Benign
This variant has been reported in ClinVar as Benign by a clinical laboratory (Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital; SCV002760434) with criteria provided. While this is a single submitter (1-star), the classification is Benign with documented criteria.
ClinVar Variation ID 1802764: Benigncriteria providedsingle submitter (SCV002760434).
Assessed · not applied
Pathogenic
PS2
No de novo data available for this variant.
PS3
No functional data available for NM_024529.5:c.424-28A>G.
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals compared to controls.
PM2
This variant is present in gnomAD v2.1 at 0.76% (2161/282588 alleles, 10 homozygotes) and in gnomAD v4.1 at 0.99% (15162/1526634 alleles, 102 homozygotes), well above the 0.1% PM2 threshold for absence from population databases.
PM6
No de novo data available for this variant.
PP1
No segregation data available for this variant.
PP3
SpliceAI max delta score is 0.07, which does not support a deleterious splicing effect.
PP4
No patient phenotype or clinical data available for this case.
PP5
ClinVar classifies this variant as Benign, not Pathogenic.
Benign
BS2
No specific observation in healthy adult controls documented for this variant in the context of full penetrance expected at early age.
BS3
No functional data demonstrating no damaging effect for this variant.
BS4
No segregation data available for non-segregation with disease in affected family members.
BP2
No data on observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP5
No case data available for an alternative molecular basis of disease.
N/A · 7
PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.00993165; MAF= 0.99317%, 15162/1526634 alleles, homozygotes = 102) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0138679; MAF= 1.38679%, 403/29060 alleles, homozygotes = 3); grpmax FAF= 0.011466.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.00764718; MAF= 0.76472%, 2161/282588 alleles, homozygotes = 10) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.013229; MAF= 1.32290%, 137/10356 alleles, homozygotes = 0); grpmax FAF= 0.0105605.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00890239930517859, 164/18422 alleles, homozygotes = 3).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.99%
· 15162 / 1,526,634
102 hom · FAF 1.1%
102 hom · FAF 1.1%
Ashkenazi Jewish 403 / 29,060 |
1.4% 3 hom |
European (Finnish) 789 / 63,974 |
1.2% 5 hom |
European (non-Finnish) 12802 / 1,100,320 |
1.2% 88 hom |
Remaining individuals 519 / 59,528 |
0.87% 3 hom |
Middle Eastern 36 / 5,880 |
0.61% |
Admixed American 304 / 59,898 |
0.51% 1 hom |
South Asian 172 / 89,392 |
0.19% 1 hom |
African/African American 137 / 73,218 |
0.19% 1 hom |
+ 2 not observed (Amish, East Asian)
gnomAD v2.1
0.76%
· 2161 / 282,588
10 hom · FAF 1.1%
10 hom · FAF 1.1%
Ashkenazi Jewish 137 / 10,356 |
1.3% |
European (Finnish) 285 / 25,116 |
1.1% 2 hom |
European (non-Finnish) 1428 / 129,084 |
1.1% 6 hom |
Remaining individuals 56 / 7,218 |
0.78% |
Admixed American 159 / 35,394 |
0.45% 1 hom |
South Asian 59 / 30,548 |
0.19% 1 hom |
African/African American 37 / 24,920 |
0.15% |
+ 1 not observed (East Asian)
gnomAD Canada 🇨🇦
0.89%
· 164 / 18,422
3 hom · FAF 1%
3 hom · FAF 1%
Ashkenazi Jewish 12 / 832 |
1.4% |
European (non-Finnish) 138 / 11,742 |
1.2% 3 hom |
Middle Eastern 1 / 144 |
0.69% |
Remaining individuals 6 / 1,138 |
0.53% |
Latino/Admixed American 4 / 838 |
0.48% |
South Asian 2 / 1,362 |
0.15% |
African/African American 1 / 1,020 |
0.098% |
+ 2 not observed (East Asian, European (Finnish))
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1802764)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR