NM_006758.2:c.132+18del is an intronic deletion (intron 2, +18) in U2AF1. It is absent from gnomAD v4.1 (0/6520 alleles), meeting PM2 at moderate strength.1 SpliceAI predicts no splice impact for this variant (max delta = 0.00), meeting BP4 at supporting benign strength.2 PVS1 is not applicable: this intronic variant does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice site) under ClinGen SVI PVS1 recommendations (PMC6185798). SpliceAI corroborates absence of splice effect.3 The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, de novo reports, or segregation data are available.4 With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting and insufficient to classify as likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.5
U2AF1
Final classification
VUS
U2AF1 c.132+18del · p.?
U2AF1
NM_006758.2:c.132+18del is an intronic deletion (intron 2, +18) in U2AF1. It is absent from gnomAD v4.1 (0/6520 alleles), meeting PM2 at moderate strength.
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
U2AF1 c.132+18del
PM2 + BP4
→
VUS
3
pvs1_variant_assessmentspliceai ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_006758.2 · variants mapped to exon structure
U2AF1
NM_006758.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
NM_006758.2:c.132+18del is absent from gnomAD v4.1 (0/6520 alleles, AF = 0.0%), gnomAD v2.1, and gnomAD-Canada. This is consistent with PM2: absent from population databases at a frequency below 0.1%.
gnomAD v4.1: 0/6520 alleles (AF = 0.0%)gnomAD v2.1: absentgnomAD-Canada v1.0: absent
✓
BP4
supporting
Benign
SpliceAI predicts no splice impact for NM_006758.2:c.132+18del (max delta score = 0.00). For an intronic variant, the relevant computational evidence is splice prediction, and the sole applicable in silico tool indicates no effect. Other in silico tools (REVEL, BayesDel) are not applicable to non-SNV variants.
SpliceAI max delta = 0.00 — no predicted donor gaindonor lossacceptor gain
Assessed · not applied
Pathogenic
PS2
No de novo occurrence data are available for NM_006758.2:c.132+18del.
PS3
No well-established in vitro or in vivo functional studies have been performed for NM_006758.2:c.132+18del.
PS4
No case-control or cohort data are available to assess whether the prevalence of NM_006758.2:c.132+18del is significantly increased in affected individuals versus controls.
PM1
NM_006758.2:c.132+18del is located in intron 2 (+18), which is not within a characterized mutational hotspot or critical functional domain of U2AF1.
PM6
No assumed de novo occurrence (without confirmation of paternity/maternity) has been reported for NM_006758.2:c.132+18del in any database or publication.
PP1
No cosegregation data are available for NM_006758.2:c.132+18del.
PP3
No computational evidence supports a deleterious effect.
PP4
No patient phenotype or family history data are available to assess whether the proband's clinical presentation is specific for a U2AF1-related disorder.
PP5
NM_006758.2:c.132+18del is absent from ClinVar.
Benign
BA1
NM_006758.2:c.132+18del is absent from gnomAD v4.1 (0/6520 alleles, AF = 0.0%).
BS1
NM_006758.2:c.132+18del is absent from gnomAD (0/6520 alleles, AF = 0.0%).
BS2
No data are available regarding observation of NM_006758.2:c.132+18del in healthy adults with full penetrance expected at an early age.
BS3
No well-established in vitro or in vivo functional studies have been performed demonstrating no damaging effect for NM_006758.2:c.132+18del.
BS4
No cosegregation data are available to assess lack of segregation with disease for NM_006758.2:c.132+18del.
BP2
No data are available regarding observation of NM_006758.2:c.132+18del in trans with a pathogenic variant in a fully penetrant recessive disorder, or in cis with a pathogenic variant in a dominant disorder.
BP5
No alternative molecular basis for disease has been identified in the proband that would explain the phenotype independent of NM_006758.2:c.132+18del.
BP6
NM_006758.2:c.132+18del is absent from ClinVar.
N/A · 9
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/6520 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/370 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 6,520
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links