NM_018062.3:c.580A>G

FANCL · NP_060532.2:p.(Ile194Val) · NM_018062.3

GRCh37: chr2:58392970 T>C · GRCh38: chr2:58165835 T>C

Gene: FANCL Transcript: NM_018062.3

Final call

VUS

BP4 supporting benign

Variant details

Gene

FANCL

Transcript

NM_018062.3

Protein

NP_060532.2:p.(Ile194Val)

gnomAD AF

0.0001455937747819191 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_018062.3:c.580A>G (p.Ile194Val) is a missense variant in exon 8 of FANCL, a Fanconi anemia pathway gene.

This variant is present in population databases: 68 of 282,780 alleles in gnomAD v2.1 (AF 0.024%) and 235 of 1,614,080 alleles in gnomAD v4.1 (AF 0.015%), including one homozygous individual in v4.1.

Multiple in silico predictors support a benign effect: REVEL score 0.049, BayesDel score -0.583, and SpliceAI max delta score 0.00.

The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (Labcorp Genetics, Fulgent Genetics) with no expert panel classification.

No variant-specific functional studies, case-control data, de novo observations, or segregation data are available.

The only criterion met is BP4 (supporting benign) based on consistent in silico predictions of no impact.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): a single supporting benign criterion (BP4) is insufficient to classify as likely benign. The variant remains a variant of uncertain significance.

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	PVS1 applies only to null variants (nonsense, frameshift, canonical splice). NM_018062.3:c.580A>G is a missense variant (p.Ile194Val) in exon 8 and is not predicted to cause loss of function via nonsense-mediated decay or canonical splice disruption.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	PS1 requires a different nucleotide change at the same codon that produces the same amino acid change and is known to be pathogenic. No alternative nucleotide substitution at c.580 resulting in p.Ile194Val has been identified or reported as pathogenic.
PS2	Not assessed	No de novo data are available for this variant. Confirmed de novo occurrence requires parental testing with confirmed maternity and paternity.
PS3	Not met	No variant-specific functional studies were identified. In silico predictors (REVEL 0.049, BayesDel -0.583) uniformly predict a benign effect. OncoKB reports no reviewed functional evidence for this variant.	revel bayesdel oncokb
PS4	Not met	No case-control studies or statistical enrichment data are available for this variant. The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories, but no case counts or odds ratios are provided.	clinvar
PS5	Not met	PS5 requires a different pathogenic missense change at the same amino acid residue. No pathogenic missense variant at codon 194 (Ile194) has been identified in ClinVar or the literature.	pm5_candidates
PM1	Not met	Residue 194 is not located within a statistically significant mutational hotspot and does not lie in a well-established functional domain where pathogenic variants cluster and benign variants are absent.
PM2	Not met	This variant is present in population databases. In gnomAD v2.1, it is observed in 68 of 282,780 alleles (AF 0.024%) with highest subpopulation frequency of 0.154% in South Asian. In gnomAD v4.1, it is observed in 235 of 1,614,080 alleles (AF 0.015%) including one homozygous individual. The South Asian subpopulation frequency (0.15%) exceeds the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variants have been identified at codon 194 (Ile194) to serve as comparator variants for PM5.	pm5_candidates
PM6	Not assessed	No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed.
PP1	Not assessed	No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not assessed	Insufficient gene-level constraint data are available to determine whether FANCL has a low rate of benign missense variation. PP2 requires gene-specific missense constraint metrics (e.g., missense z-score) that are not available in this assessment.
PP3	Not met	Multiple in silico predictors uniformly suggest a benign effect. REVEL score is 0.049 (benign-predicting, well below typical PP3 threshold of >0.5). BayesDel score is -0.583 (benign-predicting). SpliceAI predicts no splicing impact (max delta score 0.00). No computational tool supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No specific patient phenotype information is available for independent evaluation. While FANCL is associated with Fanconi anemia, PP4 requires detailed phenotypic data supporting the specific diagnosis in the proband.
PP5	Not met	PP5 requires a reputable source to have classified the variant as pathogenic. ClinVar reports this variant as Uncertain significance by two clinical laboratories (Labcorp Genetics, Fulgent Genetics). No expert panel or reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in any general population. The highest observed population frequency is 0.154% in the South Asian subpopulation (gnomAD v2.1), which is well below the 1% threshold.	gnomad_v2
BS1	Not met	BS1 requires an allele frequency >0.3% for a disorder expected to be rarer than the observed frequency. The highest observed population frequency is 0.154% in South Asian (gnomAD v2.1), below the 0.3% threshold. The single homozygote in gnomAD v4.1 is noted but does not independently satisfy BS1.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult homozygous state for a fully penetrant recessive disorder with early onset. One homozygous individual is present in gnomAD v4.1, but a single observation in a population database without clinical confirmation is insufficient to meet BS2. Additional homozygous observations or confirmed healthy adult status would be required.	gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect. No variant-specific functional assays are available. In silico predictions (REVEL 0.049, BayesDel -0.583) suggest a benign effect but do not constitute well-established functional studies.	revel bayesdel oncokb
BS4	Not assessed	No segregation data are available. BS4 requires lack of cosegregation with disease in affected family members.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. FANCL is a Fanconi anemia gene in which missense variants are a known pathogenic mechanism, including documented founder missense variants in the South Asian population. BP1 does not apply.	pvs1_gene_context
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No phasing data are available for this variant.
BP4	Met	Multiple lines of computational evidence uniformly predict no impact on the gene product. REVEL score 0.049 (strongly benign-predicting), BayesDel score -0.583 (benign-predicting), and SpliceAI max delta 0.00 (no predicted splicing impact). All available in silico tools support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	BP5 requires identification of an alternate molecular basis for disease in a case harboring this variant. No data are available regarding alternate molecular diagnoses in individuals carrying this variant.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign. ClinVar reports this variant as Uncertain significance. No clinical laboratory or expert panel has classified it as benign or likely benign.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splicing impact. NM_018062.3:c.580A>G is a missense variant (p.Ile194Val) and is not synonymous. BP7 is not applicable.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution and does not involve an in-frame indel.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. No phasing data are available, and this criterion is not trivially assessable for this substitution.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length change. This variant is a single-nucleotide substitution resulting in a missense change, not a protein length alteration.

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