Variant Report |

Variant classification summary

PRPF8 · NP_006436.3:p.(Gly643=) · NM_006445.3

GRCh37: chr17:1580914 G>A · GRCh38: chr17:1677620 G>A

Gene: PRPF8 Transcript: NM_006445.3

Final call

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Gly643=)

gnomAD AF

0.00035193334085115824 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006445.3:c.1929C>T (p.Gly643=) is a synonymous variant in PRPF8 with no predicted splice impact (SpliceAI max delta 0.10).

2

This variant is present in gnomAD v2.1 at an overall allele frequency of 0.059% (167/282,738 alleles) with a grpmax filtering allele frequency of 0.524% in the African/African American population, exceeding the 0.3% threshold for BS1.

3

In gnomAD v4.1, the variant is observed at an overall frequency of 0.035% (568/1,613,942 alleles) with a grpmax FAF of 0.629% and 3 homozygous individuals, confirming it is established in the general population at frequencies inconsistent with a fully penetrant pathogenic variant.

4

ClinVar classifies this variant as Benign (2 clinical laboratories) and Likely benign (1 clinical laboratory), with a 2-star review status (criteria provided, multiple submitters, no conflicts). Three independent clinical laboratories have reached a benign or likely benign conclusion.

5

Based on the generic ACMG/AMP 2015 framework, the variant meets BS1 (supporting benign), BS2 (supporting benign), BP4 (supporting benign), and BP7 (supporting benign), totaling 4 supporting benign criteria, consistent with a classification of Likely Benign.

Final determination:

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.1929C>T is a synonymous variant (p.Gly643=) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework
PS1	N/A	PS1 applies to variants producing the same amino acid change as an established pathogenic variant. This synonymous variant produces no amino acid change.
PS2	Not met	No de novo confirmation data are available for this variant.
PS3	Not met	No variant-specific functional data were identified for NM_006445.3:c.1929C>T. The literature reviewed contains no experimental characterization of this synonymous variant.
PS4	Not met	No case-control or prevalence data are available comparing affected versus unaffected individuals for this variant.
PS5	N/A	PS5 is not a standard generic ACMG/AMP 2015 criterion. No gene-specific VCEP defines PS5 for PRPF8.
PM1	Not met	No statistically significant hotspot was identified at this residue in cancerhotspots.org, and while PRPF8 encodes a core spliceosome component, there is no evidence that this synonymous position falls within a critical functional domain where synonymous changes are known to be pathogenic.
PM2	Not met	While the overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) is below the 0.1% PM2 threshold, the grpmax filtering allele frequency is elevated (0.524% v2.1, 0.629% v4.1) with 3 homozygotes observed in v4.1, indicating this variant is well-established in certain populations and does not meet the intent of PM2 as a rare variant criterion.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same residue. This variant is synonymous (p.Gly643=) and cannot be assessed for same-residue missense comparator semantics.
PM6	Not met	No de novo observation has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a synonymous variant.
PP3	Not met	Multiple computational predictors do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.10), and REVEL/BayesDel scores are not available for this synonymous variant.	spliceai
PP4	Not met	No proband phenotype or family history data are available for evaluation.
PP5	Not met	ClinVar reports this variant as Benign/Likely benign (2-star, criteria provided, multiple submitters, no conflicts). PP5 requires a reputable source reporting the variant as pathogenic; this does not apply.	clinvar
BA1	Not met	The overall gnomAD allele frequency (0.059% v2.1, 0.035% v4.1) and grpmax filtering allele frequency (0.524% v2.1, 0.629% v4.1) are both below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Met	The grpmax filtering allele frequency exceeds the 0.3% threshold for BS1 (0.524% in gnomAD v2.1; 0.629% in gnomAD v4.1), and 3 homozygotes are observed in v4.1, indicating this variant is more common than expected for a fully penetrant dominant disorder.	gnomad_v2 gnomad_v4
BS2	Met	Three homozygous individuals for this variant are observed in gnomAD v4.1 (total 568 alleles, 3 homozygotes). For a gene associated with autosomal dominant retinitis pigmentosa, the presence of homozygous individuals in a population database is inconsistent with a highly penetrant pathogenic variant.	gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating a benign effect were identified for this variant.
BS4	Not met	No family segregation data demonstrating lack of co-segregation with disease are available.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are a known disease mechanism. This is a synonymous variant.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splice alteration (max delta 0.10, below the 0.2 threshold), and the variant is synonymous with no amino acid change. REVEL and BayesDel are not applicable.	spliceai
BP5	Not met	No evidence that an alternative molecular basis for disease has been identified in a case carrying this variant.
BP6	Not met	ClinVar reports this variant as Benign/Likely benign with a 2-star review status (criteria provided, multiple submitters, no conflicts), but this does not meet the 3-star expert panel threshold required for BP6 application under the generic ACMG framework.	clinvar
BP7	Met	This is a synonymous variant (p.Gly643=) at a nucleotide position that is not highly conserved, with SpliceAI predicting no significant splice impact (max delta 0.10). The high population frequency in the African population (AF 0.62–0.68%) with 3 homozygotes in gnomAD v4.1 further supports that this nucleotide position tolerates variation.	spliceai gnomad_v2 gnomad_v4

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