Variant classification summary

NM_006445.3:c.2631G>A

PRPF8 · NP_006436.3:p.(Ala877=) · NM_006445.3

GRCh37: chr17:1579270 C>T · GRCh38: chr17:1675976 C>T

Gene: PRPF8 Transcript: NM_006445.3

Final call

Likely Benign

BS1 supporting benign BS2 supporting benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Ala877=)

gnomAD AF

0.002499349450440515 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006445.3:c.2631G>A is a synonymous variant (p.Ala877=) in PRPF8 with SpliceAI max delta = 0.00, predicting no splicing impact, satisfying BP7.

2

Multiple lines of computational evidence, including SpliceAI (max delta = 0.00) and the synonymous nature of the variant, show no predicted damaging effect, satisfying BP4.

3

This variant is present at a population frequency of 0.45% (1273/282848 alleles) in gnomAD v2.1, exceeding the 0.3% threshold for BS1.

4

The variant has been observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, satisfying BS2.

5

This variant has been reported in ClinVar as Benign by three clinical laboratories (ClinVar Variation ID: 321901), consistent with all benign criteria assessed.

6

No published literature identifies NM_006445.3:c.2631G>A in association with disease; all papers reviewed discuss the gene at a general level or address unrelated genes and variants.

7

The variant is classified as Likely Benign under the generic ACMG/AMP 2015 framework based on BS1, BS2, BP4, and BP7 (4 supporting benign criteria). The high population frequency (4.68% in African/African American) and numerous homozygotes (up to 86 in v4.1) strongly support that this is a benign polymorphism.

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	This is a synonymous variant (p.Ala877=) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	PS1 applies to missense variants where the same amino acid change has been established as pathogenic. This is a synonymous variant with no amino acid change.
PS2	Not met	No de novo observation reported for this variant. The high population frequency (0.45% overall in gnomAD v2.1; 4.68% in African/African American) is inconsistent with a de novo disease-causing variant.	gnomad_v2 gnomad_v4
PS3	Not met	No functional studies have been performed on this specific synonymous variant. SpliceAI predicts no splicing impact (max delta = 0.00). No REVEL or BayesDel scores are available for this synonymous change.	spliceai
PS4	Not met	No evidence of enrichment in affected individuals versus controls. The variant is present at substantial population frequency (0.45% v2.1, 0.25% v4.1; 4.68% in African/African American), inconsistent with a rare disease-causing variant.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 requires the same amino acid change as a previously established pathogenic missense variant. This is a synonymous variant (p.Ala877=) with no amino acid change.
PM1	Not met	This synonymous variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org), nor is there evidence that this residue position disrupts a critical functional domain. SpliceAI predicts no splicing impact.
PM2	Not met	This variant is present in gnomAD at frequencies exceeding the PM2 threshold of <0.1%: v2.1 overall AF=0.45% (1273/282848 alleles), v4.1 overall AF=0.25% (4034/1614020 alleles).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same residue. This is a synonymous variant (p.Ala877=) with no amino acid residue context; no comparator missense candidates can be identified.
PM6	Not met	No de novo observation has been reported for this variant in any individual with disease. The high population frequency is inconsistent with de novo pathogenicity.	gnomad_v2
PP1	Not met	No segregation data are available for this variant in affected families.
PP2	N/A	PP2 applies to missense variants in genes where missense is an established disease mechanism. This is a synonymous variant, not a missense variant.
PP3	Not met	In silico predictors are neutral: SpliceAI max delta = 0.00 predicts no splicing impact. REVEL and BayesDel scores are not available for this synonymous variant. No computational evidence supports a damaging effect.	spliceai
PP4	Not met	No specific phenotypic data link this variant to disease. The variant is a common synonymous change observed in population databases at substantial frequency.	gnomad_v2 gnomad_v4
PP5	Not met	ClinVar classification is Benign (not Pathogenic). PP5 requires a reputable source (3-star expert panel) classifying the variant as pathogenic. This variant is classified as Benign by 3 clinical laboratories at 1-star review status (criteria provided, single submitter), which does not satisfy PP5 requirements.	clinvar
BA1	Not met	The overall allele frequency in gnomAD v2.1 is 0.45% and in v4.1 is 0.25%, both below the BA1 threshold of >1%. Although the African/African American subpopulation frequency is elevated at 4.68% (v2.1) and 4.75% (v4.1), BA1 is assessed using the overall population allele frequency per standard practice.	gnomad_v2 gnomad_v4
BS1	Met	This variant is present at a population frequency exceeding 0.3% in gnomAD v2.1 (AF=0.45%, 1273/282848 alleles). Although gnomAD v4.1 shows a slightly lower overall frequency (AF=0.25%), the v2.1 data with 1273 allele observations including 33 homozygotes supports BS1. The variant is particularly common in the African/African American population (AF=4.68% v2.1, 4.75% v4.1).	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in the homozygous state in 33 individuals in gnomAD v2.1 and 86 individuals in gnomAD v4.1, indicating it is well-tolerated in biallelic form and inconsistent with causing a fully penetrant dominant or recessive disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed on this specific synonymous variant demonstrating no damaging effect. While SpliceAI predicts no splicing impact, this alone does not constitute the functional evidence required for BS3.
BS4	Not met	No segregation data are available showing lack of cosegregation with disease in affected families.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This is a synonymous variant, not a missense variant.
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact: SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel scores are not available for this synonymous change. The variant is synonymous and does not alter the encoded amino acid.	spliceai
BP5	Not met	No evidence that this variant has been identified in a case with an alternative molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Benign (3 clinical laboratories), but the review status is 'criteria provided, single submitter' (1-star). BP6 requires a 3-star expert panel classification to reach supporting benign strength. The current 1-star status is insufficient to apply BP6.	clinvar
BP7	Met	This is a synonymous variant (p.Ala877=) for which SpliceAI predicts no impact on splicing (max delta = 0.00). The nucleotide substitution does not create a novel splice site nor disrupt a splice consensus sequence.	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.