NM_033084.4:c.70A>G

FANCD2 · NP_149075.2:p.(Arg24Gly) · NM_033084.4

GRCh37: chr3:10074521 A>G · GRCh38: chr3:10032837 A>G

Gene: FANCD2 Transcript: NM_033084.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

FANCD2

Transcript

NM_033084.4

Protein

NP_149075.2:p.(Arg24Gly)

gnomAD AF

3.1004367895349097e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

No functional studies, segregation data, de novo observations, case-control data, or variant-specific literature evidence were identified for this variant.

Five ClinVar-associated PMIDs were reviewed; none contained variant-specific evidence for NM_033084.4:c.70A>G.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_033084.4:c.70A>G is a missense variant (p.Arg24Gly) and does not fall into the PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Generic PVS1 framework is not applicable.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No known pathogenic variant with a different nucleotide change at the same codon (Arg24) was identified to serve as a PS1 comparator.
PS2	Not assessed	No de novo observation data (with both maternity and paternity confirmed) is available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies supporting a damaging effect on the gene product were identified for this variant. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence.	oncokb
PS4	Not assessed	No case-control or enriched case prevalence data are available. The variant is extremely rare in population databases, but no affected vs. unaffected comparison data exist.	gnomad_v4 clinvar
PS5	Not met	No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Sema4) classifies the variant as uncertain significance.	clinvar
PM1	Not assessed	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No known pathogenic missense variant at the same residue (Arg24) with a different amino acid change was identified to serve as a PM5 comparator. Candidate harvesting was unsuccessful.	pm5_candidates
PM6	Not assessed	No de novo observation data (without confirmation of paternity and maternity) is available for this variant.
PP1	Not assessed	No cosegregation data with disease in affected family members is available.
PP2	Not assessed	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	Not met	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). All in silico predictors are concordant for a benign interpretation.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data specific to FANCD2-related disease are available for assessment.
PP5	Not met	No reputable source has classified this variant as pathogenic. The sole ClinVar submission (Sema4) classifies as uncertain significance. The associated ClinVar PMIDs (GeneReviews, PDQ summaries, carrier screening guidelines) are general references that do not provide variant-specific pathogenic assertions.	clinvar PMID:20301575 PMID:18197057 PMID:26389210 PMID:26389258 PMID:26389333
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), far below the BA1 threshold of >1%. BA1 is not met.	gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 3.1e-06 (0.00031%), below the BS1 threshold of >0.3% for recessive disorders. BS1 is not met.	gnomad_v4
BS2	Not assessed	No data are available on observation of this variant in healthy adult individuals with full penetrance expectation for Fanconi anemia.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on the gene product were identified for this variant.
BS4	Not assessed	No segregation data in affected families are available to assess lack of cosegregation with disease.
BP1	N/A	FANCD2 is associated with both truncating and missense pathogenic variants in Fanconi anemia. BP1 applies only when the disease mechanism is exclusively via truncating variants.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a known dominant pathogenic variant are available.
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	No reputable source classifies this variant as benign. The sole ClinVar submission (Sema4) classifies as uncertain significance. BP6 is not met.	clinvar
BP7	N/A	This is a missense variant (c.70A>G, p.Arg24Gly). BP7 applies only to synonymous or intronic variants with no predicted splice impact.
BP3	N/A	This variant is a substitution. BP3 applies only to in-frame insertions/deletions in repetitive regions.
PM3	N/A	No observation of this variant in trans with a known pathogenic variant in FANCD2 for this recessive disorder.
PM4	N/A	This is a missense substitution (p.Arg24Gly). PM4 applies only to non-repeat protein length changes (in-frame deletions/insertions, stop-loss).

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