NM_006445.3:c.3775-14del is an intronic variant (c.3775-14) in PRPF8, located 14 bases upstream of exon 25. It is not predicted to affect splicing (SpliceAI max delta = 0.00).1 This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00241% (6/248,886 alleles) and gnomAD v4.1 allele frequency 0.00112% (18/1,613,790 alleles), with no homozygotes observed.2 This variant has been classified as Benign by Labcorp Genetics (formerly Invitae) in ClinVar (Variation ID: 1921408, SCV002951453), with criteria provided by a single clinical submitter.3 No variant-specific functional studies, de novo observations, segregation data, or case-control evidence were identified for this variant. Applying the generic ACMG/AMP 2015 framework, the criteria met are PM2 (supporting) balanced against BP4 (supporting benign) and BP6 (supporting benign). With two supporting benign criteria and one supporting pathogenic criterion, the net evidence favors a likely benign classification.4
PRPF8
Final classification
Likely Benign
PRPF8 c.3775-14del · p.?
PRPF8
NM_006445.3:c.3775-14del is an intronic variant (c.3775-14) in PRPF8, located 14 bases upstream of exon 25. It is not predicted to affect splicing (SpliceAI max delta = 0.00).
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 benign, BP6 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6
Likely Benign
PRPF8 c.3775-14del
PM2 + BP4 + BP6
→
Likely Benign
Gene diagram
· NM_006445.3 · variants mapped to exon structure
PRPF8
NM_006445.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases. In gnomAD v2.1 it has an allele frequency of 0.00241% (6/248,886 alleles) and in gnomAD v4.1 an allele frequency of 0.00112% (18/1,613,790 alleles). Both are well below the 0.1% threshold for PM2 in the non-VCEP generic ACMG framework. No homozygotes are observed.
gnomAD v2.1: AF = 0.00241% (6/248886)hom = 0
✓
BP4
supporting
Benign
Computational evidence suggests this intronic variant does not impact splicing. SpliceAI predicts no splice-altering effect with a maximum delta score of 0.00, indicating the variant does not create or disrupt splice acceptor or donor sites.
SpliceAI max delta = 0.00 (no predicted acceptor gain/lossno donor gain/loss)
✓
BP6
supporting
Benign
This variant has been classified as Benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with criteria provided in ClinVar (SCV002951453; ClinVar Variation ID: 1921408). While the detailed criteria are not publicly available for independent evaluation, the classification from an established clinical laboratory supports a benign interpretation.
ClinVar classification: Benigncriteria providedsingle submitter (Labcorp Genetics/Invitae)
Assessed · not applied
Pathogenic
PVS1
NM_006445.3:c.3775-14del is an intronic variant located 14 bases upstream of exon 25 in intron 24.
PS2
No de novo observation reported in ClinVar or the available literature for this variant.
PS3
No variant-specific functional studies identified.
PS4
No case-control or prevalence data comparing affected vs.
PM1
This variant is not located in an established mutational hotspot or critical functional domain.
PM6
No de novo observation (with or without confirmed paternity/maternity) has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP3
No computational evidence supports a damaging effect.
PP4
No patient phenotype or clinical data are available to assess whether the variant is found in individuals with a phenotype specific for PRPF8-related disease.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is far below the 1% BA1 threshold.
BS1
The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is below the 0.3% BS1 threshold.
BS2
No homozygotes have been observed in gnomAD for this variant (hom = 0 in both v2.1 and v4.1).
BS3
No well-established functional studies demonstrating no damaging effect on splicing or gene product are available for this variant.
BS4
No non-segregation data are available for this variant.
BP2
No data are available on whether this variant has been observed in trans with a known pathogenic variant in a recessive disorder.
BP5
No data are available indicating this variant is found in a case with an alternative molecular basis for disease.
N/A · 7
PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.11539e-05; MAF= 0.00112%, 18/1613790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00010001; MAF= 0.01000%, 6/59994 alleles, homozygotes = 0); grpmax FAF= 4.284e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.41074e-05; MAF= 0.00241%, 6/248886 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000115801; MAF= 0.01158%, 4/34542 alleles, homozygotes = 0); grpmax FAF= 3.897e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0011%
· 18 / 1,613,790
0 hom · FAF 0.0043%
0 hom · FAF 0.0043%
Admixed American 6 / 59,994 |
0.01% |
Remaining individuals 2 / 62,494 |
0.0032% |
European (non-Finnish) 10 / 1,179,902 |
0.00085% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0024%
· 6 / 248,886
0 hom · FAF 0.0039%
0 hom · FAF 0.0039%
Admixed American 4 / 34,542 |
0.012% |
European (Finnish) 1 / 21,366 |
0.0047% |
European (non-Finnish) 1 / 112,768 |
0.00089% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1921408)
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 previously been reported in somatic cancers (COSMIC; COSV59262866, n = 4 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR