NM_006445.3:c.471T>C

PRPF8 · NP_006436.3:p.(Asp157=) · NM_006445.3

GRCh37: chr17:1585296 A>G · GRCh38: chr17:1682002 A>G

Gene: PRPF8 Transcript: NM_006445.3

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Asp157=)

gnomAD AF

1.0535409511367707e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006445.3:c.471T>C is a synonymous variant (p.Asp157=) in PRPF8 that is present at extremely low frequency in population databases (gnomAD v2.1: 6/282,676 alleles, AF=0.00212%; gnomAD v4.1: 17/1,613,606 alleles, AF=0.00105%).

SpliceAI predicts no splicing impact for this variant (max delta score = 0.00), consistent with a synonymous change that does not alter the protein sequence or mRNA processing.

This variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical laboratory, with criteria provided (ClinVar Variation ID: 1133865, SCV001672660).

No published literature identifies NM_006445.3:c.471T>C in association with disease; the sole ClinVar-cited reference (PMID:28492532, Sherloc framework paper) does not mention this specific variant.

Three supporting benign criteria (BP4, BP6, BP7) outweigh one supporting pathogenic criterion (PM2). Under ACMG/AMP 2015 combination rules (PMID:25741868), this yields a final classification of Likely benign.

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	N/A	NM_006445.3:c.471T>C is a synonymous variant (p.Asp157=) that does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	PS1 applies when a different nucleotide change at the same position has been established as pathogenic and produces the same amino acid change. This is a synonymous variant with no amino acid change; no alternative nucleotide substitution at c.471 can produce a pathogenic missense with the same amino acid consequence.
PS2	Not assessed	No de novo data are available for this variant in any reviewed source.
PS3	Not assessed	No well-established functional studies have been identified for this variant. OncoKB lists Unknown Oncogenic Effect with no supporting PMIDs for functional evidence.
PS4	Not assessed	No case-control prevalence data are available. The variant is observed at very low frequency in population databases (gnomAD), but no comparison of affected versus unaffected individuals has been performed.
PS5	Not assessed	No alternative causative variant has been identified at this locus. No published reports establish a different variant at c.471 as definitively pathogenic.
PM1	Not met	This variant is not located in a recognized mutational hotspot or well-established critical functional domain. Hotspot analysis confirms the residue is not statistically significant, and the synonymous change produces no amino acid alteration.
PM2	Met	This variant is present in gnomAD at extremely low allele frequency: 6/282,676 alleles (AF=0.00212%) in v2.1 and 17/1,613,606 alleles (AF=0.00105%) in v4.1, both well below the non-VCEP threshold of 0.1%. No homozygotes observed.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different missense change at the same residue that has been established as pathogenic. This is a synonymous variant (p.Asp157=) with no amino acid change; no same-residue missense comparator is relevant. PM5 candidate harvesting confirmed not applicable.
PM6	Not assessed	No de novo data are available for this variant. PM6 requires confirmed de novo occurrence with confirmed maternity and paternity.
PP1	Not assessed	No segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a synonymous variant (p.Asp157=), not a missense change.
PP3	Not met	No in silico tools predict a deleterious effect. SpliceAI delta score is 0.00 (no splicing impact). REVEL and BayesDel scores are not available for this variant.	spliceai
PP4	Not assessed	No patient phenotype data are available to assess specificity for a PRPF8-associated disorder.
PP5	Not met	ClinVar reports this variant as Likely benign, not pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic. No expert panel or reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	Allele frequency in gnomAD is 0.002% (v2.1) and 0.001% (v4.1), well below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency in gnomAD is 0.002% (v2.1) and 0.001% (v4.1), below the non-VCEP threshold of 0.3% for BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No homozygotes have been observed in gnomAD, and no data are available on co-occurrence with a known pathogenic variant in trans. Without observation in a healthy adult in a homozygous state or in trans with a pathogenic variant, BS2 cannot be applied.
BS3	Not assessed	No well-established functional studies demonstrate no damaging effect for this specific variant.
BS4	Not assessed	No segregation data are available to assess non-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is a synonymous variant (p.Asp157=), not a missense change.
BP2	Not assessed	No data are available on co-occurrence of this variant in trans with a known pathogenic variant or in cis with a pathogenic variant in a recessive disorder gene.
PM3	N/A	PM3 applies to recessive disorders. PRPF8-associated disorders follow autosomal dominant inheritance.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide synonymous substitution.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide synonymous substitution, not an in-frame indel.
BP4	Met	SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Multiple lines of computational evidence suggest no effect on the gene product.	spliceai
BP5	Not assessed	No data are available on an alternative molecular basis for disease in a case harboring this variant.
BP6	Met	This variant has been reported in ClinVar as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with criteria provided (SCV001672660).	clinvar
BP7	Met	This is a synonymous variant (p.Asp157=) with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. The nucleotide substitution is not predicted to affect mRNA processing.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.