NM_033084.4:c.70A>G (p.Arg24Gly) is a missense variant in exon 3 of FANCD2. The variant is extremely rare in population databases (gnomAD v4.1 AF 3.1e-06, 5/1,612,676 alleles, 0 homozygotes; absent from gnomAD v2.1 and gnomAD-Canada), meeting PM2 at supporting level.1 Multiple lines of computational evidence (REVEL 0.023, BayesDel -0.631, SpliceAI max delta 0.08) are concordant for a benign interpretation, meeting BP4 at supporting benign level.2 The variant has been reported in ClinVar (VariationID 1692057) by a single submitter (Sema4) as uncertain significance; no reputable source has classified it as pathogenic or benign.3 No functional studies, segregation data, de novo observations, case-control data, or variant-specific literature evidence were identified for this variant.4 Five ClinVar-associated PMIDs were reviewed; none contained variant-specific evidence for NM_033084.4:c.70A>G.5 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) in conflict, and no additional criteria met, the variant is classified as Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules.6
FANCD2
Final classification
VUS
FANCD2 c.70A>G · p.Arg24Gly
FANCD2
NM_033084.4:c.70A>G (p.Arg24Gly) is a missense variant in exon 3 of FANCD2.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FANCD2 c.70A>G
PM2 + BP4
→
VUS
Gene diagram
· NM_033084.4 · variants mapped to exon structure
FANCD2
NM_033084.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present at very low frequency in gnomAD v4.1 (AF 3.1e-06, 5/1,612,676 alleles, 0 homozygotes; grpmax FAF 1.24e-06), well below the PM2 threshold of <0.1%. Downgraded to supporting due to confirmed observations of 5 alleles.
gnomAD v2.1: absent. gnomAD v4.1: AF 3.1e-06 (5/1612676 alleles
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign interpretation: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact). All in silico predictors are concordant for no impact on gene product.
REVEL: 0.023 (strongly benign). BayesDel: -0.631 (benign). SpliceAI: max delta 0.08 (no splicing impact). All predictors concordant for benign interpretation.
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with a different nucleotide change at the same codon (Arg24) was identified to serve as a PS1 comparator.
PS2
No de novo observation data (with both maternity and paternity confirmed) is available for this variant.
PS3
No well-established in vitro or in vivo functional studies supporting a damaging effect on the gene product were identified for this variant.
PS4
No case-control or enriched case prevalence data are available.
PM1
Residue Arg24 is not located in a statistically significant mutational hotspot (hotspots screen negative), and no evidence establishes this as a critical well-established functional domain.
PM6
No de novo observation data (without confirmation of paternity and maternity) is available for this variant.
PP1
No cosegregation data with disease in affected family members is available.
PP2
Insufficient gene-level data to assess whether FANCD2 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease, in the absence of VCEP-specific guidance.
PP3
Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.023 (strongly benign), BayesDel score -0.631 (benign), and SpliceAI max delta 0.08 (no splicing impact).
PP4
No patient phenotype or family history data specific to FANCD2-related disease are available for assessment.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), far below the BA1 threshold of >1%.
BS1
The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), below the BS1 threshold of >0.3% for recessive disorders.
BS2
No data are available on observation of this variant in healthy adult individuals with full penetrance expectation for Fanconi anemia.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect on the gene product were identified for this variant.
BS4
No segregation data in affected families are available to assess lack of cosegregation with disease.
BP2
No data on observation of this variant in trans with a known dominant pathogenic variant are available.
BP5
No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6
No reputable source classifies this variant as benign.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.10044e-06; MAF= 0.00031%, 5/1612676 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23972e-06; MAF= 0.00042%, 5/1179324 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,612,676
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,179,324 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 1692057)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.023. BayesDel score = -0.631389.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCD2, a tumor suppressor and DNA repair protein, is infrequently altered in cancer. Germline mutations of FANCD2 are associated with the cancer pred
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR