NM_006445.3:c.3775-14delT

PRPF8 · NP_006436.3:p.? · NM_006445.3

GRCh37: chr17:1565460 GA>G · GRCh38: chr17:1662166 GA>G

Gene: PRPF8 Transcript: NM_006445.3

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.?

gnomAD AF

1.1153867603591546e-05 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_006445.3:c.3775-14del is an intronic variant located 14 bases upstream of exon 25 in intron 24. It does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants) defined by the ClinGen SVI PVS1 framework (PMC6185798). The variant does not disrupt a canonical splice site and is not predicted to cause loss of function via aberrant splicing.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Variant is intronic and does not result in an amino acid change; no protein-level comparator is possible.
PS2	Not met	No de novo observation reported in ClinVar or the available literature for this variant.	clinvar
PS3	Not met	No variant-specific functional studies identified. The variant is intronic and no experimental data demonstrating a damaging effect on splicing or gene product were found.
PS4	Not met	No case-control or prevalence data comparing affected vs. unaffected individuals are available for this variant.
PS5	N/A	Variant is intronic; no codon or amino acid position is affected for PS5 comparison.
PM1	Not met	This variant is not located in an established mutational hotspot or critical functional domain. Hotspot analysis found no significant residue enrichment and the exact variant is not listed as a recurrent somatic or germline hotspot.
PM2	Met	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 gnomad_v4
PM4	N/A	Variant is intronic and does not cause an in-frame or out-of-frame change in protein length.
PM5	N/A	Variant is intronic with no protein consequence (p.?); no same-residue comparator missense variants can be evaluated.	pm5_candidates
PM6	Not met	No de novo observation (with or without confirmed paternity/maternity) has been reported for this variant.	clinvar
PP1	Not met	No co-segregation data are available for this variant.
PP2	N/A	Variant is not a missense change; PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	No computational evidence supports a damaging effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant.	spliceai
PP4	Not met	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	Not met	No reputable source has classified this variant as pathogenic. ClinVar reports it as Benign (single submitter: Labcorp Genetics/Invitae).	clinvar
BA1	Not met	The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is far below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism by allele frequency alone.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes have been observed in gnomAD for this variant (hom = 0 in both v2.1 and v4.1). In the absence of homozygous observations in healthy adults, BS2 cannot be applied.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no damaging effect on splicing or gene product are available for this variant.	spliceai
BS4	Not met	No non-segregation data are available for this variant.
BP1	N/A	Variant is intronic, not a missense change. BP1 applies only to missense variants in genes where truncating variants are a known disease mechanism.
BP2	Not met	No data are available on whether this variant has been observed in trans with a known pathogenic variant in a recessive disorder. PRPF8-related disease is typically autosomal dominant (retinitis pigmentosa type 13).
BP3	N/A	Variant is a single-nucleotide intronic deletion, not an in-frame insertion/deletion in a repetitive region.
BP4	Met	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
BP5	Not met	No data are available indicating this variant is found in a case with an alternative molecular basis for disease.
BP6	Met	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
BP7	N/A	Variant is an intronic deletion, not a synonymous (silent) variant. BP7 applies only to synonymous variants predicted not to impact splicing.

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