Variant classification summary

NM_006445.3:c.2409G>A

PRPF8 · NP_006436.3:p.(Ala803=) · NM_006445.3

GRCh37: chr17:1579644 C>T · GRCh38: chr17:1676350 C>T

Gene: PRPF8 Transcript: NM_006445.3

Final call

Benign

BA1 stand-alone benign BP7 supporting

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Ala803=)

gnomAD AF

0.0024712911427537706 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PRPF8 NM_006445.3:c.2409G>A (p.Ala803=) variant has not been reported in ClinVar as a pathogenic germline variant and is listed there as benign.

2

This variant is common in population databases, with a highest observed allele frequency of 3.582% in gnomAD v2.1, 3.636% in gnomAD v4.1, and 3.627% in gnomAD-Canada, which is above the 1% BA1 threshold.

3

In silico splice prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.05.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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 variant is a synonymous change, NM_006445.3:c.2409G>A (p.Ala803=), and does not fall into the generic PVS1 null-variant categories. Available evidence therefore does not support applying PVS1.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	N/A	This criterion applies to a different nucleotide change causing the same amino acid substitution. This variant is synonymous and does not change the amino acid.	clinvar
PS2	Not assessed	No confirmed de novo data were identified for this variant.
PS3	Not assessed	No published functional studies specific to this variant were identified that demonstrate a damaging effect.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals compared with controls. Instead, the variant is common in population databases, which argues against case enrichment.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM1	Not met	Available evidence does not support location in a mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a significant hotspot at this residue.	hotspots
PM2	Not met	This variant is not absent from population databases. Its allele frequency is 0.494% in gnomAD v2.1, 0.247% in gnomAD v4.1, and 0.212% in gnomAD-Canada, all above the usual rarity threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder context.
PM4	N/A	This criterion applies to protein length changes from in-frame insertions, deletions, or stop-loss variants. This variant is a synonymous substitution and does not alter protein length.	clinvar
PM5	N/A	PM5 applies to a novel missense change at a residue with a different pathogenic missense change. This variant is synonymous, and the PM5 review artifact did not support classic same-residue PM5 use.	pm5_candidates
PM6	Not assessed	No assumed de novo data were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is used for missense variants in genes with low benign missense variation and a common missense disease mechanism. This variant is not missense.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified showing that the clinical presentation is highly specific for a disorder caused by this variant.
PP5	Not assessed	Although ClinVar contains benign submissions for this variant, PP5 is not applied because this is not pathogenic supportive evidence and external assertions alone were not used as primary criterion evidence.	clinvar
BA1	Met	This variant is too common for a pathogenic germline variant. The highest observed population frequency is 3.582% in African/African American individuals in gnomAD v2.1, 3.636% in African/African American individuals in gnomAD v4.1, and 3.627% in the afr population in gnomAD-Canada, all above the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not assessed	The population frequency is above the BS1 threshold, but BS1 was not additionally applied because BA1 is already met based on a frequency above 1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	This variant is observed with homozygotes in population databases, which is reassuring, but phenotype-free adult observations and penetrance context were not established well enough here to apply BS2 independently.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	No published functional studies specific to this variant were identified that demonstrate no damaging effect.	oncokb
BS4	Not assessed	No segregation data were identified showing lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the main disease mechanism. This variant is not missense.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis for any disorder context.
BP3	Not assessed	No evidence was identified that this variant is an in-frame change in a repetitive region without known function.
BP4	N/A	BP4 is generally used for missense variants when multiple computational tools support no impact on the protein. This variant is synonymous, so splice prediction is addressed under BP7 instead.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular basis that fully explains the phenotype independently of this variant.
BP6	Not assessed	ClinVar contains benign submissions for this variant, but BP6 was not applied because external assertions alone were not used as primary criterion evidence.	clinvar
BP7	Met	This is a synonymous variant, NM_006445.3:c.2409G>A (p.Ala803=), and available splice prediction does not support an effect on splicing. SpliceAI shows a maximum delta score of 0.05, consistent with no significant splice impact.	clinvar 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.