About FANCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCL c.1A>G, p.(Met1?)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Moderate
PVS1 · moderate
c.1A>G is an initiation codon variant (ATG>GTG, p.Met1Val) in FANCL, a gene where loss-of-function is an established disease mechanism for Fanconi anemia. No alternative in-frame ATG start codon is present in exon 1 (residues 1-32: MAVTEASLLRQCPLLLPQNRSKTVYEGFISAQ). Per ClinGen SVI PVS1 recommendations (PMC6185798), initiation codon variants without an alternative start codon in the same exon qualify for PVS1 at moderate strength. The pipeline-generated pvs1_variant_assessment incorrectly assigned this variant to the 'other' bucket; this adjudication overrides that assignment because c.1A>G is unequivocally a start codon loss, which is an ACMG-recognized null variant type.
PM2Supporting
PM2 · supporting
NM_018062.3:c.1A>G is absent from gnomAD v2.1 (0/250,782 alleles) and present at extremely low frequency in gnomAD v4.1 (AF=0.00037%, 6/1,614,100 alleles, no homozygotes). The maximum observed subpopulation frequency is in European (non-Finnish) at 0.00051% (6/1,180,000). The grpmax filtering allele frequency (FAF) is 1.83e-06. All frequencies are well below the PM2 threshold of <0.1%. The variant is also absent from gnomAD-Canada v1.0. Assigned supporting rather than moderate strength due to trace presence (6 alleles) in gnomAD v4.1.
PP5Supporting
PP5 · supporting
Two clinical diagnostic laboratories have independently classified NM_018062.3:c.1A>G as likely pathogenic or pathogenic in ClinVar (Variation ID: 1691887; VCV001691887). Labcorp Genetics/Invitae (SCV005703968) classifies as Pathogenic with criteria provided (citing PM2, PS3). Fulgent Genetics (SCV005658736) classifies as Likely pathogenic (clinical testing). The ClinVar aggregate classification is Pathogenic/Likely pathogenic with review status 'criteria provided, multiple submitters, no conflicts' (2 stars). However, these classifications are from single submitters without expert panel review, and the evidence underlying the cited criteria is not independently verifiable from the case materials. Full-text review of the cited PMIDs did not confirm variant-specific evidence. Assigned supporting strength per ACMG/AMP PP5 guidance for reputable source reporting without independent verification.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM2 supporting, PP5 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,614,100 alleles
gnomAD v4.1: 6 / 1,614,100 alleles. Recorded AF 3.71724e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16190 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
1 Likely pathogenic · 1 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_018062.3:c.1A>G (p.Met1Val) is an initiation codon variant in FANCL, where loss-of-function is an established mechanism for autosomal recessive Fanconi anemia. The variant abolishes the initiator methionine with no alternative start codon in exon 1, qualifying for PVS1 at moderate strength per ClinGen SVI recommendations (PMC6185798).
The variant is absent from gnomAD v2.1 (0/250,782 alleles) and present at extremely low frequency in gnomAD v4.1 (AF=0.00037%, 6/1,614,100 alleles, no homozygotes), meeting PM2 at supporting strength.
Two clinical laboratories have independently classified this variant as Likely pathogenic and Pathogenic in ClinVar (Variation ID 1691887, 2-star review status), satisfying PP5 at supporting strength. However, full-text review of the PMIDs cited in these ClinVar submissions did not confirm variant-specific evidence.
No variant-specific functional studies (PS3), de novo observations (PS2/PM6), segregation data (PP1), or case-control data (PS4) were identified for this variant in the reviewed literature.
The ACMG/AMP evidence tally of 1 moderate (PVS1) and 2 supporting (PM2, PP5) criteria does not reach the Likely Pathogenic threshold (requires 1 moderate + 4 supporting or 2 moderate + 2 supporting). This variant is classified as a Variant of Uncertain Significance (VUS) by formal ACMG/AMP 2015 combination rules, bordering on Likely Pathogenic given the initiation codon loss mechanism and concordant clinical laboratory classifications.
No criteria match.
Met · 3
PVS1 Moderatec.1A>G is an initiation codon variant (ATG>GTG, p.Met1Val) in FANCL, a gene where loss-of-function is an established disease mechanism for Fanconi anemia. No alternative in-frame ATG start codon is present in exon 1 (residues 1-32: MAVTEASLLRQCPLLLPQNRSKTVYEGFISAQ). Per ClinGen SVI PVS1 recommendations (PMC6185798), initiation codon variants without an alternative start codon in the same exon qualify for PVS1 at moderate strength. The pipeline-generated pvs1_variant_assessment incorrectly assigned this variant to the 'other' bucket; this adjudication overrides that assignment because c.1A>G is unequivocally a start codon loss, which is an ACMG-recognized null variant type. Details ▾Hide ▴
Evidence considered
- FANCL loss-of-function is an established disease mechanism for Fanconi anemia
- supported by truncating mutations reported in FA patients (PMID:25754594) and zebrafish knockout models (PMID:30540754)
- c.1A>G alters the initiator ATG to GTG
- predicted to abolish translation initiation
- protein consequence annotated as NP_060532.2:p.(Met1?)
- No alternative in-frame methionine codon exists in exon 1 (residues 1-32 confirmed from NP_060532.2 sequence)
- ClinGen SVI PVS1 decision tree (PMC6185798) supports PVS1_Moderate for initiation codon variants without alternative start codons in the same exon
Still missing
- No experimental confirmation that this specific variant abolishes FANCL protein expression
- No functional complementation data for c.1A>G
- pipeline pvs1_variant_assessment misclassified this as 'other' bucket — manual override applied
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessmentPMID:25741868 ↗PMID:25754594 ↗PMID:30540754 ↗
PM2 SupportingNM_018062.3:c.1A>G is absent from gnomAD v2.1 (0/250,782 alleles) and present at extremely low frequency in gnomAD v4.1 (AF=0.00037%, 6/1,614,100 alleles, no homozygotes). The maximum observed subpopulation frequency is in European (non-Finnish) at 0.00051% (6/1,180,000). The grpmax filtering allele frequency (FAF) is 1.83e-06. All frequencies are well below the PM2 threshold of <0.1%. The variant is also absent from gnomAD-Canada v1.0. Assigned supporting rather than moderate strength due to trace presence (6 alleles) in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/250
- 782 alleles (0%)
- gnomAD v4.1: 6/1
- 614
- 100 alleles (0.00037%)
- grpmax FAF=1.83e-06
- gnomAD-Canada v1.0: 0 alleles
- Highest subpopulation: NFE 0.00051% — all well below 0.1% PM2 cutoff
Sources
PP5 SupportingTwo clinical diagnostic laboratories have independently classified NM_018062.3:c.1A>G as likely pathogenic or pathogenic in ClinVar (Variation ID: 1691887; VCV001691887). Labcorp Genetics/Invitae (SCV005703968) classifies as Pathogenic with criteria provided (citing PM2, PS3). Fulgent Genetics (SCV005658736) classifies as Likely pathogenic (clinical testing). The ClinVar aggregate classification is Pathogenic/Likely pathogenic with review status 'criteria provided, multiple submitters, no conflicts' (2 stars). However, these classifications are from single submitters without expert panel review, and the evidence underlying the cited criteria is not independently verifiable from the case materials. Full-text review of the cited PMIDs did not confirm variant-specific evidence. Assigned supporting strength per ACMG/AMP PP5 guidance for reputable source reporting without independent verification. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 1691887: Pathogenic/Likely pathogenic
- 2 stars
- criteria provided by multiple submitters with no conflicts
- Labcorp Genetics/Invitae (SCV005703968): Pathogenic
- clinical testing
- cites PM2 and PS3
- Fulgent Genetics (SCV005658736): Likely pathogenic
- Sema4 (SCV002527276): Likely pathogenic
- curation method (not usable for classification
- but contributes to aggregate)
Still missing
- No expert panel (ENIGMA
- ClinGen VCEP) review of this variant
- Underlying evidence for ClinVar classifications could not be independently verified from cited PMIDs
- Cited PMIDs do not contain variant-specific data for NM_018062.3:c.1A>G
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo observation of NM_018062.3:c.1A>G has been reported in the literature. None of the reviewed publications document a de novo occurrence with confirmed paternity and maternity. Details ▾Hide ▴
Still missing
- No trio-based sequencing data available for de novo assessment
PS3 No variant-specific functional studies were identified. Full-text review of seven publications and abstract review of eight additional publications returned no direct experimental characterization of NM_018062.3:c.1A>G. The ClinVar submission from Labcorp Genetics (SCV005703968) acknowledges that 'functional studies have not been performed to directly test the effect of this variant on FANCL protein function.' OncoKB classifies as 'Likely Loss-of-function' computationally and cites zebrafish gene-level knockout studies (PMID:20661450, PMID:30540754) and FANCL domain structural studies (PMID:26149689), none of which tested this specific variant. Domain-level inference from these papers supports PM1-type reasoning but does not satisfy PS3's requirement for variant-specific experimental data. Details ▾Hide ▴
Evidence considered
- Invitae/Labcorp submission specifically states no direct functional testing was performed for this variant
- OncoKB 'Likely Loss-of-function' is a computational classification
- not experimental evidence
- Zebrafish FANCL knockout studies (PMID:20661450
- PMID:30540754) are gene-level
- not variant-specific
- FANCL domain structure studies (PMID:26149689
- PMID:27986371) do not test c.1A>G
Still missing
- No experimental functional assay has been performed on NM_018062.3:c.1A>G
- Absence of complementation studies
- FANCD2 monoubiquitination assays
- or MMC sensitivity testing for this specific variant
Sources
PS4 No case-control or cohort data comparing the prevalence of NM_018062.3:c.1A>G in affected individuals versus the general population has been published. The variant is present at extremely low frequency in gnomAD (0.00037%), but there is no statistically powered comparison in an affected cohort. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 6/1
- 614
- 100 alleles (AF=0.00037%)
- No published case-control data available
Still missing
- No affected-individual cohort statistics for this variant
Sources
PM1 The variant affects the initiator methionine at the very N-terminus of FANCL. While the start codon is critical for protein expression, cancerhotspots.org reports no statistically significant hotspot at this residue. FANCL contains three well-characterized functional domains (E2-like fold/ELF at N-terminus, DRWD central domain, RING C-terminal domain), but the initiation codon itself does not lie within a domain region characterized by an excess of pathogenic missense variants. The loss of all protein domains resulting from start codon loss is more appropriately captured by PVS1 than by PM1 domain-level criteria. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not in a statistically significant hotspot
- PMID:26149689 describes FANCL 3-domain structure (ELF
- DRWD
- RING) but does not identify codon 1 as within a pathogenic missense cluster
Sources
PM6 No de novo confirmation of NM_018062.3:c.1A>G has been reported in the literature. None of the reviewed publications include trio-based sequencing data demonstrating a de novo occurrence of this variant. Details ▾Hide ▴
Still missing
- No trio or parent-of-origin testing data available
PP1 No segregation data are available for NM_018062.3:c.1A>G. None of the reviewed publications report co-segregation of this variant with disease in affected family members. Details ▾Hide ▴
Still missing
- No family-based segregation analysis published
PP2 FANCL disease mechanism is loss-of-function, not missense-predominant. The variant is a start codon loss (functionally null), not a standard missense. PP2 is designed for missense variants in genes where missense is a common disease mechanism; FANCL pathogenicity is predominantly driven by truncating/null variants. Details ▾Hide ▴
Evidence considered
- PMID:25754594 reports truncating FANCL mutations (c.268del
- c.430del) as the disease mechanism for severe FA
- ClinGen SVI PVS1 gene context confirms LOF mechanism for FANCL
Sources
PP3 REVEL score 0.227 falls below the typical pathogenic threshold (>0.5). BayesDel score -0.184843 is negative, predicting benign. SpliceAI max delta score is 0.00, predicting no splicing impact. However, standard in silico missense predictors (REVEL, BayesDel) are not calibrated for initiation codon loss variants; their scores do not reliably predict the functional consequence of abolishing translation initiation. HCI prior probability is not available for FANCL. Multiple lines of in silico evidence do not converge on a pathogenic prediction for this variant type. Details ▾Hide ▴
Evidence considered
- REVEL: 0.227 (below pathogenic threshold)
- BayesDel: -0.184843 (benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: not available for FANCL
Still missing
- No in silico tool specifically calibrated for initiation codon loss prediction
Sources
PP4 While Fanconi anemia is a highly specific clinical syndrome, its genetic etiology involves at least 22 genes (FANCA through FANCW). PP4 requires a highly specific phenotype for a disease with a single genetic etiology; Fanconi anemia is genetically heterogeneous and does not meet this criterion. No patient-specific phenotype data were available in the case materials for independent evaluation. Details ▾Hide ▴
Evidence considered
- ClinVar lists conditions: Fanconi anemia
- Fanconi anemia complementation group L
- Fanconi anemia has at least 22 causal genes — not a single genetic etiology
Still missing
- No patient-specific phenotype or clinical history available
Sources
BA1 The maximum allele frequency of NM_018062.3:c.1A>G in gnomAD is 0.00051% (European non-Finnish, v4.1), far below the BA1 threshold of >1%. The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.00051% (NFE)
- gnomAD v2.1: 0%
- BA1 threshold: >1% — not approached
Sources
BS1 The maximum allele frequency of NM_018062.3:c.1A>G in gnomAD is 0.00051% (European non-Finnish, v4.1), far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.00051% (NFE)
- BS1 threshold: >0.3% — not approached
Sources
BS2 No observation of NM_018062.3:c.1A>G in a healthy adult individual has been documented outside of population databases. The 6 heterozygous carriers in gnomAD v4.1 lack phenotype data and cannot be confirmed as healthy adults with full penetrance age. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 6 heterozygous carriers without phenotype annotation
- No published report of this variant in a confirmed healthy adult
Still missing
- Phenotype data unavailable for gnomAD carriers
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate that NM_018062.3:c.1A>G has no deleterious effect on protein function or splicing. OncoKB computationally classifies the variant as 'Likely Loss-of-function,' which is contrary to a benign interpretation. No experimental data support a benign functional outcome for this initiation codon loss. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Loss-of-function
- Likely Oncogenic — not consistent with benign effect
- No experimental studies testing this specific variant for normal function
Still missing
- No benign functional studies exist for this variant
Sources
BS4 No lack of segregation data has been reported for NM_018062.3:c.1A>G. BS4 requires documented non-segregation with disease in affected family members, which is absent from the literature. Details ▾Hide ▴
Still missing
- No family-based non-segregation data available
BP2 No evidence demonstrates that NM_018062.3:c.1A>G has been observed in trans with a known pathogenic FANCL variant in a healthy individual. No phase-resolved genotype data are available. Details ▾Hide ▴
Still missing
- No phasing or trans-configuration data available
BP4 While BayesDel (-0.184843) and REVEL (0.227) scores are low and SpliceAI predicts no splicing impact (delta 0.00), these in silico tools are designed and calibrated for standard missense variants. They are not validated for predicting the functional consequence of initiation codon loss variants, which operate through a fundamentally different mechanism (abolition of translation initiation rather than amino acid substitution effect). The computational scores do not constitute reliable evidence that the variant has no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL 0.227: below pathogenic threshold but not validated for initiation codon variants
- BayesDel -0.185: benign prediction but not validated for initiation codon variants
- SpliceAI 0.00: no splice impact predicted
Sources
BP5 No observation of NM_018062.3:c.1A>G in a case where an alternative molecular basis for disease was identified has been reported. BP5 requires documented co-occurrence with an alternative pathogenic variant explaining the phenotype. Details ▾Hide ▴
Still missing
- No co-occurrence data with alternative molecular diagnoses
BP6 No reputable source classifies NM_018062.3:c.1A>G as benign or likely benign. ClinVar reports Pathogenic/Likely pathogenic from two clinical laboratories. OncoKB classifies as Likely Oncogenic. All available curated sources indicate a pathogenic or likely pathogenic interpretation. Details ▾Hide ▴
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change as an established pathogenic missense variant. This is an initiation codon loss variant (p.Met1Val), not a standard missense; the initiation codon loss mechanism is fundamentally distinct and not amenable to PS1 comparison. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to identify a classic same-residue missense comparator for PM5 evaluation. The protein consequence p.(Met1?) does not resolve to a standard missense amino acid change at a defined residue position. The automated pm5_candidates pipeline confirmed this and recommended against applying PM5. No alternative pathogenic missense at codon 1 of FANCL has been identified. Details ▾Hide ▴
Evidence considered
- Automated PM5 candidate harvesting returned 0 candidates
- protein consequence p.(Met1?) does not parse to standard residue semantics
Sources
pm5_candidates
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants are known to cause disease. NM_018062.3:c.1A>G is an initiation codon loss variant, functionally equivalent to a null/truncating variant rather than a standard missense. The disease mechanism for FANCL is loss-of-function through truncating/null variants, consistent with this variant's predicted effect. BP1 is not applicable to null variants. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_018062.3:c.1A>G is a non-synonymous initiation codon change (p.Met1Val), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires an established pathogenic missense variant at the same codon with a different amino acid change. The initiation codon (ATG) is fundamentally distinct from standard missense codons; no alternative pathogenic initiation codon variant has been established at codon 1 of FANCL. This criterion is not applicable to start codon loss variants. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FANCL
- Transcript
- NM_018062.3
- Coding (HGVS c.)
- NM_018062.3:c.1A>G
- Protein (HGVS p.)
- NP_060532.2:p.(Met1?)
- GRCh38
- chr2:58241313 T>C
- GRCh37
- chr2:58468448 T>C
- ClinVar
- 1691887
Gene diagram
Every interpreted variant in FANCL, mapped onto the exon structure of NM_018062.3. Select a row to find it on the plot.
FANCLNM_018062.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in FANCL
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
6 / 1,614,100 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1
0 / 250,782 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,614,100 alleles · 0 hom · FAF 1.8e-06
| European (non-Finnish)6 / 1,180,000 | 5.1e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0 · 0 / 250,782 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71724e-06; MAF= 0.00037%, 6/1614100 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08475e-06; MAF= 0.00051%, 6/1180000 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16190 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.227
- BayesDel
- -0.185
How the predictions were used
PP3 REVEL score 0.227 falls below the typical pathogenic threshold (>0.5). BayesDel score -0.184843 is negative, predicting benign. SpliceAI max delta score is 0.00, predicting no splicing impact. However, standard in silico missense predictors (REVEL, BayesDel) are not calibrated for initiation codon loss variants; their scores do not reliably predict the functional consequence of abolishing translation initiation. HCI prior probability is not available for FANCL. Multiple lines of in silico evidence do not converge on a pathogenic prediction for this variant type. Details ▾Hide ▴
Evidence considered
- REVEL: 0.227 (below pathogenic threshold)
- BayesDel: -0.184843 (benign prediction)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: not available for FANCL
Still missing
- No in silico tool specifically calibrated for initiation codon loss prediction
Sources
BP4 While BayesDel (-0.184843) and REVEL (0.227) scores are low and SpliceAI predicts no splicing impact (delta 0.00), these in silico tools are designed and calibrated for standard missense variants. They are not validated for predicting the functional consequence of initiation codon loss variants, which operate through a fundamentally different mechanism (abolition of translation initiation rather than amino acid substitution effect). The computational scores do not constitute reliable evidence that the variant has no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL 0.227: below pathogenic threshold but not validated for initiation codon variants
- BayesDel -0.185: benign prediction but not validated for initiation codon variants
- SpliceAI 0.00: no splice impact predicted
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_018062.3:c.1A>G is a non-synonymous initiation codon change (p.Met1Val), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.227. BayesDel score = -0.184843.
8 paper records listed. 3 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 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.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological guideline document and does not discuss any specific FANCL variants.→ PVS1 Does not name this variant
Source detail
Location Full text reviewed; no variant-specific content
-
PMID 25754594 ↗Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association.Reports two novel FANCL truncating mutations (c.268del, p.Leu90Phefs*6 and c.430del, p.Ser144Leufs*6) in three patients with severe Fanconi anemia overlapping VACTERL association. Both mutations cause NMD and loss of FANCD2 monoubiquitination; functional complementation with wild-type FANCL rescued the phenotype. NM_018062.3:c.1A>G was not among the mutations identified.→ PVS1 Does not name this variant
Source detail
a single nucleotide deletion (NM_018062.3:c.268del; p.Leu90Phefs*6) in exon 4 of FANCL
Location Full text reviewed; two other FANCL variants (c.268del, c.430del) reported but not c.1A>G
-
PMID 30540754 ↗Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.Used multiplexed CRISPR/Cas9 to generate loss-of-function knockout mutants for 17 FA pathway genes in zebrafish (including fancl). Generated two independent indel mutant lines for fancl predicted to cause premature truncations. This is a systematic gene-level knockout study; no specific human FANCL missense or initiation codon variants were tested.→ PVS1 Does not name this variant
Source detail
Location Full text reviewed; fancl knockout zebrafish generated but no human c.1A>G variant tested
Other recorded publications
-
PMID 20661450 ↗Sex reversal in zebrafish fancl mutants is caused by Tp53-mediated germ cell apoptosis.Reports sex reversal phenotype in zebrafish fancl homozygous mutants. This is a gene-level functional study demonstrating that Fancl is required for germ cell development; no specific human FANCL variants were tested or reported.Does not name this variant
-
PMID 22720145 ↗Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing.Describes a next-generation sequencing approach for comprehensive mutation detection in Fanconi anemia genes. No NM_018062.3:c.1A>G was identified or reported among the sequenced cases.Does not name this variant
-
PMID 26149689 ↗The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.Miles JA et al. · 2015Characterizes the three-domain structure of FANCL (E2-like fold/ELF, DRWD, RING) and demonstrates that the ELF domain interacts with ubiquitin to regulate FA pathway activity. This is a structural and biochemical study of wild-type FANCL domains; no disease-associated variants were functionally tested.Does not name this variant
-
PMID 29335925 ↗Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.Fostira F et al. · 2018Evaluates the clinical utility of multi-gene panel testing in male breast cancer, including FANCL among the genes analyzed. Does not report NM_018062.3:c.1A>G as an identified variant; reports infrequent deleterious mutations in non-BRCA2 genes.Does not name this variant
-
PMID 29625052 ↗Pathogenic Germline Variants in 10,389 Adult Cancers.Huang KL et al. · 2018Large-scale pan-cancer analysis of pathogenic germline variants across 10,389 cases from 33 cancer types. Identified 853 pathogenic/likely pathogenic variants across multiple cancer predisposition genes. FANCL was among the genes analyzed but NM_018062.3:c.1A>G was not specifically reported or discussed.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,614,100 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely pathogenic · 1 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1691887/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-58468448-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-58241313-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-58241313-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_018062.3%3Ac.1A%3…
- OncoKB ↗www.oncokb.org/gene/FANCL/M1?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FANCL+c.1A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71724e-06; MAF= 0.00037%, 6/1614100 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08475e-06; MAF= 0.00051%, 6/1180000 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16190 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory). (ClinVarID = 1691887)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.227. BayesDel score = -0.184843.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.