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FANCD2c.206-1G>ALikely pathogenic
Print report
Variant interpretation report

FANCD2 c.206-1G>A, p.?

NM_033084.4:c.206-1G>A NP_149075.2:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FANCD2

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

NM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1. FANCD2 loss of function is an established disease mechanism for Fanconi anemia and cancer predisposition. Under the ClinGen SVI PVS1 decision framework (PMC6185798), canonical ±1,2 splice variants in genes with established LOF disease mechanism are assigned PVS1 at strong weight.

PM2Moderate
PM2 · moderate

NM_033084.4:c.206-1G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. The allele frequency is 0.0% across all population databases, meeting the PM2 threshold of <0.1% for a gene with established germline disease association.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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 strong, PM2 moderate; combination = 1 strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.950 maximum delta

Recorded SpliceAI maximum delta score: 0.950. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 3 not met · 16 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1 (PVS1_Strong). FANCD2 loss of function is an established germline disease mechanism for Fanconi anemia and cancer predisposition, supporting PVS1 at strong weight under PMC6185798.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Moderate), consistent with a rare pathogenic variant in a gene with established germline disease association.

SpliceAI predicts a strong splice effect (max delta 0.95, acceptor loss 0.95) and BayesDel scores 0.66 (damaging). These in silico predictions support pathogenicity but are not stacked as PP3 per PMC6185798 guidance to avoid double-counting with PVS1 for canonical splice variants.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one Strong criterion (PVS1) plus one Moderate criterion (PM2) meets the threshold for Likely Pathogenic.

Met · 2

PVS1 StrongNM_033084.4:c.206-1G>A disrupts the canonical splice acceptor at intron 3 position -1. FANCD2 loss of function is an established disease mechanism for Fanconi anemia and cancer predisposition. Under the ClinGen SVI PVS1 decision framework (PMC6185798), canonical ±1,2 splice variants in genes with established LOF disease mechanism are assigned PVS1 at strong weight. Details ▾Hide ▴
Evidence considered
  • FANCD2 germline loss of function is a well-established disease mechanism supported by multiple publications (PMID:27285993
  • PMID:29659569
  • PMID:29376519)
  • Variant disrupts the canonical splice acceptor consensus sequence at position c.206-1 (intron 3)
  • ClinGen SVI PVS1 framework (PMC6185798) assigns strong weight to canonical splice variants in genes with established LOF mechanism
Still missing
  • Confirm NM_033084.4 is the clinically relevant transcript for the patient indication
  • No RNA studies available to confirm aberrant splicing
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 ModerateNM_033084.4:c.206-1G>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. The allele frequency is 0.0% across all population databases, meeting the PM2 threshold of <0.1% for a gene with established germline disease association. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AC=0 across all populations)
  • Absent from gnomAD v4.1 (AC=0 across all populations)
  • Absent from gnomAD-Canada v1.0 (AC=0)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 3 · evaluated, threshold not reached

BA1 NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% in gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_033084.4:c.206-1G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0.0%, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele frequency 0.0% in gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 In silico predictions are uniformly damaging: SpliceAI predicts strong splice disruption (max delta score 0.95), and BayesDel score is 0.66, exceeding the damaging threshold. No benign computational prediction is available to support BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.95 (damaging)
  • BayesDel score 0.66 (damaging threshold >0.27)
Sources
spliceai ↗bayesdel

Not assessed · 16 · no assessment recorded

PS1 No known pathogenic variant at the same nucleotide position with the same predicted amino acid change is available for comparison. This canonical splice variant has no established pathogenic comparator. Details ▾Hide ▴
Still missing
  • No ClinVar or literature entries for any variant at c.206-1
PS2 No de novo occurrence data are available for NM_033084.4:c.206-1G>A. The variant has not been reported in any publication or clinical database. Details ▾Hide ▴
Still missing
  • No parental testing data available
  • No de novo reports in ClinVar or literature
PS3 No functional studies evaluating the impact of NM_033084.4:c.206-1G>A on splicing or protein function have been identified in the literature. Details ▾Hide ▴
Still missing
  • No RNA splicing assays
  • minigene reporter studies
  • or protein functional studies available for this variant
PS4 No case-control studies or prevalence data comparing affected versus unaffected individuals are available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort studies reporting this variant
PM1 No well-established mutational hotspot or critical functional domain has been identified for FANCD2 at the c.206-1 splice acceptor region. The variant is intronic and does not map to a characterized functional domain. Details ▾Hide ▴
Still missing
  • FANCD2 lacks a curated ClinGen domain specification for PM1 application
PM6 No de novo occurrence data, parental confirmation, or maternity/paternity testing is available for NM_033084.4:c.206-1G>A. Details ▾Hide ▴
Still missing
  • No de novo reports or parental testing data in ClinVar or literature
PP1 No cosegregation data are available for NM_033084.4:c.206-1G>A. No family studies have been reported. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient phenotype information is available to assess whether the clinical presentation is specific for FANCD2-related disease. Details ▾Hide ▴
Still missing
  • Patient phenotype and clinical indication not provided
PP5 The variant is absent from ClinVar. No reputable clinical source has reported NM_033084.4:c.206-1G>A as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no submissions exist
Still missing
  • No clinical laboratory or expert panel classification available
Sources
clinvar ↗
BS2 No data are available on observation of this variant in healthy adult individuals. FANCD2-related Fanconi anemia typically presents in childhood; adult-onset phenotypes are not well characterized for this variant. Details ▾Hide ▴
Still missing
  • No systematic healthy adult screening data available
BS3 No functional studies demonstrating a benign effect of NM_033084.4:c.206-1G>A on splicing or protein function have been identified. Details ▾Hide ▴
Still missing
  • No RNA or protein functional studies available
BS4 No segregation data are available to assess whether the variant fails to cosegregate with disease in affected families. Details ▾Hide ▴
Still missing
  • No family segregation studies available
BP2 No data are available on whether NM_033084.4:c.206-1G>A has been observed in trans with a known pathogenic FANCD2 variant. Details ▾Hide ▴
Still missing
  • No phase or trans configuration data available
BP5 No case has been identified where NM_033084.4:c.206-1G>A is observed in an individual with an alternative molecular cause for the phenotype. Details ▾Hide ▴
Still missing
  • No alternative molecular cause data available
BP6 The variant is absent from ClinVar. No reputable source has classified NM_033084.4:c.206-1G>A as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
Still missing
  • No clinical laboratory benign classification available
Sources
clinvar ↗
PS5 No family-based segregation or phase data are available for NM_033084.4:c.206-1G>A. Details ▾Hide ▴
Still missing
  • No family studies or phase information available
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/ANM_033084.4:c.206-1G>A is a canonical splice variant with unknown protein consequence (p.?). No same-residue missense comparator is available; classic PM5 semantics cannot be applied. Details ▾Hide ▴

No further detail was recorded.

PP2 N/ANM_033084.4:c.206-1G>A is a canonical splice site variant, not a missense change. PP2 applies only to missense variants in genes with low tolerance for missense variation. Details ▾Hide ▴

No further detail was recorded.

PP3 N/ASpliceAI predicts a deleterious splice effect (max delta score 0.95 with acceptor loss 0.95, donor loss 0.67). BayesDel score is 0.66 (damaging). However, the ClinGen SVI PVS1 framework (PMC6185798) explicitly states that in silico splice prediction evidence should not be double-counted with PVS1 for canonical splice variants. Since PVS1 is applied at strong weight for the splice defect, PP3 for the same splice prediction evidence is not stacked. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.95 (acceptor loss 0.95
  • donor loss 0.67)
  • BayesDel score 0.66 (damaging)
  • PP3 evidence is captured by PVS1 for canonical splice variants under PMC6185798
  • not stacked
Sources
spliceai ↗bayesdel
BP1 N/ANM_033084.4:c.206-1G>A is a canonical splice site variant, not a missense variant. BP1 applies only to missense variants in genes where truncating variants are the primary disease mechanism. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ANM_033084.4:c.206-1G>A is a single nucleotide substitution, not an in-frame insertion or deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_033084.4:c.206-1G>A is a canonical splice site variant, not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FANCD2
Transcript
NM_033084.4
Coding (HGVS c.)
NM_033084.4:c.206-1G>A
Protein (HGVS p.)
NP_149075.2:p.?
GRCh38
chr3:10034468 G>A
GRCh37
chr3:10076152 G>A

Gene diagram

Every interpreted variant in FANCD2, mapped onto the exon structure of NM_033084.4. Select a row to find it on the plot.

FANCD2NM_033084.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp
0.950
SpliceAI acceptor gainat -74 bp
0.460
SpliceAI donor lossat +68 bp
0.670
SpliceAI donor gainat +430 bp
0.000
Pangolin splice lossmagnitude shown
-0.770
Pangolin splice gain
0.090

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

BP4 In silico predictions are uniformly damaging: SpliceAI predicts strong splice disruption (max delta score 0.95), and BayesDel score is 0.66, exceeding the damaging threshold. No benign computational prediction is available to support BP4. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.95 (damaging)
  • BayesDel score 0.66 (damaging threshold >0.27)
Sources
spliceai ↗bayesdel
PP3 N/ASpliceAI predicts a deleterious splice effect (max delta score 0.95 with acceptor loss 0.95, donor loss 0.67). BayesDel score is 0.66 (damaging). However, the ClinGen SVI PVS1 framework (PMC6185798) explicitly states that in silico splice prediction evidence should not be double-counted with PVS1 for canonical splice variants. Since PVS1 is applied at strong weight for the splice defect, PP3 for the same splice prediction evidence is not stacked. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.95 (acceptor loss 0.95
  • donor loss 0.67)
  • BayesDel score 0.66 (damaging)
  • PP3 evidence is captured by PVS1 for canonical splice variants under PMC6185798
  • not stacked
Sources
spliceai ↗bayesdel
BP7 N/ANM_033084.4:c.206-1G>A is a canonical splice site variant, not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.95). BayesDel score = 0.66.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.950 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.95). BayesDel score = 0.66.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).