About FANCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FANCL c.524C>T, p.(Ala175Val)
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no damaging effect: REVEL score 0.089 (benign), BayesDel score -0.494 (benign), and SpliceAI predicts no splicing impact (max delta 0.04).
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: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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
37 / 1,613,586 alleles
gnomAD v4.1: 37 / 1,613,586 alleles. Recorded AF 2.29303e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89017e-05; MAF= 0.00389%, 11/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.96994e-05; MAF= 0.00697%, 9/129126 alleles, homozygotes = 0); grpmax FAF= 3.42e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
4 Uncertain significance · 1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV99288152, n = 1 times).
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.
29 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is absent or extremely rare in large population cohorts: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), meeting PM2 at supporting level.
Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089, BayesDel score -0.494, and SpliceAI predicts no splicing impact (max delta 0.04), meeting BP4 at supporting level.
The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories and Likely benign by 1 clinical laboratory (ClinVar Variation ID: 898372). No expert panel classification is available.
The variant is a missense substitution (p.Ala175Val) and does not qualify for PVS1. No functional studies, segregation data, case-control comparisons, or de novo observations were identified for this variant.
Applying generic ACMG/AMP 2015 final combination rules (PMID:25741868): PM2_supporting and BP4_supporting provide conflicting lines of evidence with no other criteria met. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.00389% (11/282,764 alleles) and v4.1 allele frequency 0.00229% (37/1,613,586 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.89e-5 (11/282
- 764 alleles
- 0 homozygotes)
- gnomAD v4.1: AF=2.29e-5 (37/1
- 613
- 586 alleles
Sources
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect: REVEL score 0.089 (benign), BayesDel score -0.494 (benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.089 (benign
- below 0.5 threshold)
- BayesDel: -0.494 (benign
- negative score)
- SpliceAI max delta: 0.04 (no predicted splicing impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS3 No well-established functional studies demonstrating a damaging effect for NM_018062.3:c.524C>T were identified. No reviewed publication contained variant-specific functional data. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data identified in literature or databases
Still missing
- No functional assays performed on this specific missense variant
PM1 The variant is not located in a known mutational hotspot or well-established critical functional domain. Hotspot analysis confirmed residue 175 is not statistically significant. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue 175 not significant
- no enrichment signal
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089 (well below the 0.5 threshold for pathogenicity), BayesDel score -0.494 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.089 (benign)
- BayesDel: -0.494 (benign)
- SpliceAI max delta: 0.04 (no splice impact)
Sources
PP5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (4 clinical laboratories) and Likely benign (1 clinical laboratory); no expert panel classification available. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 US submissions
- 1 LB submission
- no expert panel review
- no pathogenic classification
Sources
BA1 The highest population allele frequency (gnomAD v2.1 European non-Finnish: 0.00697%) is far below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
- Max population AF: 6.97e-5 (0.00697%) in European non-Finnish
- well below 1% BA1 threshold
Sources
BS1 The highest population allele frequency (0.00697%) is below the 0.3% threshold required for BS1. Details ▾Hide ▴
BS2 No homozygous observations in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes). The variant has not been observed in a healthy adult homozygous state. Details ▾Hide ▴
BP2 FANCL is associated with disease through biallelic loss-of-function variants, not exclusively through missense changes. BP2 applies only to genes where disease is exclusively caused by missense variants. Details ▾Hide ▴
Evidence considered
- FANCL disease mechanism includes LoF
- BP2 requires missense-only gene-disease relationship
Sources
pvs1_gene_context
BP6 One ClinVar submitter (Ambry Genetics) classifies this variant as Likely benign, but four other clinical laboratories classify it as Uncertain significance. The single-submitter Likely benign classification does not meet the BP6 threshold for a reputable source with strong evidence of benign impact. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 LB classification (Ambry Genetics) vs 4 US classifications
- insufficient consensus for BP6
Sources
Not assessed · 12 · no assessment recorded
PS1 No evidence of a different nucleotide change at codon 175 resulting in the same Ala175Val amino acid substitution that has been established as pathogenic. Details ▾Hide ▴
Still missing
- No same-amino-acid pathogenic comparator identified
PS2 No de novo data with confirmed maternity and paternity available for this variant. Details ▾Hide ▴
Still missing
- No de novo observations with parental confirmation available
PS4 No case-control data or sufficient patient observations to assess whether the variant prevalence differs significantly between affected individuals and controls. Details ▾Hide ▴
Still missing
- No case-control studies or enriched patient cohort data available
PM6 No de novo observations (with or without confirmed parentage) available for this variant. Details ▾Hide ▴
Still missing
- No de novo reports available
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
- No family or co-segregation studies available
PP2 Insufficient data to determine whether FANCL has a low rate of benign missense variation and a preponderance of pathogenic missense variants, which would be required for PP2 application. Details ▾Hide ▴
Still missing
- No gene-level constraint or missense pathogenicity enrichment data for FANCL
PP4 No patient-specific phenotype or family history data available for review. Details ▾Hide ▴
Still missing
- No case-level phenotypic data provided
BS3 No well-established functional studies demonstrating no damaging effect for this specific variant were identified. Details ▾Hide ▴
Still missing
- No variant-specific benign functional evidence available
BS4 No segregation data available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
BP1 While FANCL is a gene in which biallelic loss-of-function variants cause Fanconi anemia, insufficient data are available to determine that primarily truncating (rather than missense) variants are the established cause of disease, which is required to apply BP1 to this missense variant. Details ▾Hide ▴
Evidence considered
- FANCL LoF causes Fanconi anemia
- but distribution of pathogenic variant types not characterized for BP1 assessment
Still missing
- Need systematic review of FANCL pathogenic variant types (missense vs truncating ratio)
Sources
pvs1_gene_context
BP5 No alternative missense variant at codon 175 with a benign classification was identified in ClinVar. Details ▾Hide ▴
Still missing
- No benign missense comparator at codon 175 identified
PS5 No alternative pathogenic missense variant at codon 175 identified for comparison via ClinVar. Details ▾Hide ▴
Still missing
- No known pathogenic missense variant at codon 175 in FANCL
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Ala175Val); it does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant does not qualify for PVS1 null-variant framework
Sources
PM3 N/APre-marked as skip; PM3 assessment deferred. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASubstitution variant; PM4 applies to non-repeat in-frame deletions/insertions and stop-loss variants only. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator missense variants at Ala175 with established pathogenicity were identified. PM5 candidate search returned no qualified comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-residue pathogenic or likely pathogenic comparators found
BP3 N/ASubstitution variant; BP3 applies to in-frame indels only. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.524C>T, p.Ala175Val), not a silent/synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants only
Identifiers
- Gene
- FANCL
- Transcript
- NM_018062.3
- Coding (HGVS c.)
- NM_018062.3:c.524C>T
- Protein (HGVS p.)
- NP_060532.2:p.(Ala175Val)
- GRCh38
- chr2:58198610 G>A
- GRCh37
- chr2:58425745 G>A
- ClinVar
- 898372
- COSMIC
- COSV99288152
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FANCL
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
37 / 1,613,586 alleles
AF 2.29e-05 · 0 homozygotes · FAF 6.61e-05
gnomAD v2.1
11 / 282,764 alleles
AF 3.89e-05 · 0 homozygotes · FAF 3.42e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.3e-05 · 37 / 1,613,586 alleles · 0 hom · FAF 6.6e-05
| Admixed American8 / 60,002 | 0.00013 |
| European (non-Finnish)27 / 1,179,588 | 2.3e-05 |
| Remaining individuals1 / 62,494 | 1.6e-05 |
| African/African American1 / 75,024 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,764 alleles · 0 hom · FAF 3.4e-05
| European (non-Finnish)9 / 129,126 | 7e-05 |
| Admixed American2 / 35,424 | 5.6e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.29303e-05; MAF= 0.00229%, 37/1613586 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000133329; MAF= 0.01333%, 8/60002 alleles, homozygotes = 0); grpmax FAF= 6.615e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89017e-05; MAF= 0.00389%, 11/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.96994e-05; MAF= 0.00697%, 9/129126 alleles, homozygotes = 0); grpmax FAF= 3.42e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.089
- BayesDel
- -0.494
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no damaging effect: REVEL score 0.089 (benign), BayesDel score -0.494 (benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.089 (benign
- below 0.5 threshold)
- BayesDel: -0.494 (benign
- negative score)
- SpliceAI max delta: 0.04 (no predicted splicing impact)
Sources
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.089 (well below the 0.5 threshold for pathogenicity), BayesDel score -0.494 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta 0.04). Details ▾Hide ▴
Evidence considered
- REVEL: 0.089 (benign)
- BayesDel: -0.494 (benign)
- SpliceAI max delta: 0.04 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.524C>T, p.Ala175Val), not a silent/synonymous variant. BP7 applies only to synonymous variants without predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- BP7 is for synonymous variants only
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.089. BayesDel score = -0.494214.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015Policy statement on whole-genome sequencing in newborn screening programmes. Does not discuss FANCL or NM_018062.3:c.524C>T.Does not name this variant
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PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.Edwards JG et al. · 2015Joint professional society statement on expanded carrier screening in reproductive medicine. Mentions Fanconi anemia group C in a carrier screening guideline table but does not discuss FANCL or NM_018062.3:c.524C>T.Does not name this variant
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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.This is the ACMG/AMP 2015 standards and guidelines for variant interpretation. Does not discuss FANCL or NM_018062.3:c.524C>T.Does not name this variant
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PMID 20301575 ↗Fanconi Anemia.GeneReviews clinical summary on Fanconi anemia. This is a gene-level overview of FA; the specific variant NM_018062.3:c.524C>T was not identified in the available abstract or metadata.Does not name this variant
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PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014Workshop report on the appropriateness of newborn screening for alpha-1-antitrypsin deficiency. Does not discuss FANCL or NM_018062.3:c.524C>T.Does not name this variant
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PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013Recommendations on including newborn screening bloodspot collection device serial numbers on birth certificates. Does not discuss FANCL or NM_018062.3:c.524C>T.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
37 / 1,613,586 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
4 Uncertain significance · 1 Likely benign
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/898372/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-58425745-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-58198610-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-58198610-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_018062.3%3Ac.524C…
- OncoKB ↗www.oncokb.org/gene/FANCL/A175V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=150999554
- 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= 2.29303e-05; MAF= 0.00229%, 37/1613586 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000133329; MAF= 0.01333%, 8/60002 alleles, homozygotes = 0); grpmax FAF= 6.615e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.89017e-05; MAF= 0.00389%, 11/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.96994e-05; MAF= 0.00697%, 9/129126 alleles, homozygotes = 0); grpmax FAF= 3.42e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 898372)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.089. BayesDel score = -0.494214.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FANCL, an E3 ubiquitin ligase involved in DNA repair, is infrequently altered in cancer. Germline mutations of FANCL are associated with the cancer pr
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99288152, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.