Variant classification summary

NM_006445.3:c.5352C>T

PRPF8 · NP_006436.3:p.(Asn1784=) · NM_006445.3

GRCh37: chr17:1561844 G>A · GRCh38: chr17:1658550 G>A

Gene: PRPF8 Transcript: NM_006445.3

Final call

Likely Benign

BS2 supporting benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

PRPF8

Transcript

NM_006445.3

Protein

NP_006436.3:p.(Asn1784=)

gnomAD AF

0.001677332334950746 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006445.3:c.5352C>T (p.Asn1784=) is a synonymous variant in PRPF8 with no predicted splicing impact (SpliceAI max delta = 0.04; BP7).

2

Multiple lines of computational evidence suggest no deleterious effect, with no significant splice alteration predicted (BP4).

3

The variant is present in gnomAD at appreciable frequency (v2.1: 0.089%; v4.1: 0.168%) and has been observed in the homozygous state in multiple individuals (2 homozygotes in v2.1; 5 in v4.1), supporting a benign interpretation (BS2).

4

ClinVar reports this variant as Likely benign / Benign across multiple clinical testing laboratories (5 of 7 submissions), with no reputable source reporting it as pathogenic (BP6).

5

No pathogenic criteria are met. Four supporting benign criteria are satisfied (BS2, BP4, BP6, BP7), satisfying the generic ACMG/AMP 2015 threshold for Likely benign (≥2 supporting benign criteria).

6

No published literature was identified that specifically mentions NM_006445.3:c.5352C>T; the four PMIDs associated with the ClinVar record do not contain variant-specific evidence.

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.5352C>T is a synonymous variant (p.Asn1784=) that does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI max delta score of 0.04 predicts no significant splice alteration. PVS1 is reserved for variants with a clear loss-of-function mechanism.	pvs1_generic_framework spliceai
PS1	N/A	This is a synonymous variant that does not alter the amino acid sequence. PS1 requires a different nucleotide change producing the same amino acid change as an established pathogenic missense variant.
PS2	Not assessed	No de novo data with confirmed paternity and maternity were identified for this variant.
PS3	Not assessed	No variant-specific functional studies were identified. SpliceAI delta score of 0.04 does not support a deleterious functional effect. No publications report experimental characterization of NM_006445.3:c.5352C>T.	spliceai
PS4	Not assessed	No case-control data comparing variant prevalence in PRPF8-related disease cases versus controls were identified.
PS5	N/A	PS5 is not defined in the generic ACMG/AMP 2015 framework (PMID:25741868). This criterion exists only in select VCEP/CSPEC frameworks and is not applicable under the current generic_acmg framework mode.	generic_acmg_combination_rules
PM1	N/A	This is a synonymous variant that does not alter the amino acid sequence. PM1 is designed for missense variants located in a mutational hotspot or critical functional domain where pathogenic missense variants cluster and benign variation is absent.
PM2	Not met	This variant is present in gnomAD at appreciable frequency, exceeding the 0.1% non-VCEP PM2 threshold. In gnomAD v2.1, the total allele frequency is 0.089% (252/282,852 alleles, 2 homozygotes) with a grpmax FAF of 0.149%. In gnomAD v4.1, the total allele frequency is 0.168% (2,706/1,613,276 alleles, 5 homozygotes) with a grpmax FAF of 0.206%. The grpmax filtering allele frequency exceeds 0.1% in both builds.	gnomad_v2 gnomad_v4
PM5	N/A	This is a synonymous variant. PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously established. No amino acid change is present to evaluate.
PM6	Not assessed	No de novo data (without confirmation of paternity and maternity) were identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant in affected families.
PP2	N/A	This is a synonymous variant. PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta = 0.04). REVEL and BayesDel scores are not available for this synonymous variant, as these tools assess missense substitution effects. No computational tool predicts a deleterious consequence.	spliceai
PP4	Not assessed	No proband phenotype or clinical data were available to evaluate whether the patient's presentation is highly specific for PRPF8-related disease.
PP5	Not met	ClinVar classifies this variant as Likely benign / Benign (ClinVarID: VCV000196868), with 5 of 7 submissions reporting a benign or likely benign classification. No reputable source reports this variant as pathogenic. PP5 requires a reputable source to have reported the variant as pathogenic without independent evidence being available.	clinvar
BA1	Not met	The maximum population allele frequency is 0.213% in the European (non-Finnish) subpopulation of gnomAD v4.1. This does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population allele frequency is 0.213% in the European (non-Finnish) subpopulation of gnomAD v4.1. This does not exceed the 0.3% non-VCEP BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in the homozygous state in population databases: 2 homozygotes in gnomAD v2.1 and 5 homozygotes in gnomAD v4.1 including across multiple ancestry groups (European non-Finnish, African/African American, South Asian). For a gene associated with autosomal dominant retinitis pigmentosa, observation of multiple apparently healthy homozygous individuals supports a benign interpretation.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this specific variant. SpliceAI alone, while predicting no impact (delta 0.04), does not constitute a well-established functional study.	spliceai
BS4	Not assessed	No segregation data were available to assess lack of segregation with disease.
BP1	N/A	This is a synonymous variant. BP1 is designed for missense variants in genes where truncating variants are the primary pathogenic mechanism.
BP2	Not assessed	No phasing data were available to determine whether this variant has been observed in cis with a pathogenic variant or in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest no impact. SpliceAI predicts no significant splice alteration (max delta = 0.04, well below the 0.1 threshold for any predicted effect). The synonymous nature of the variant (p.Asn1784=) is consistent with no protein-level consequence.	spliceai
BP5	Not assessed	No data were identified showing this variant in a case with an alternate molecular basis for disease.
BP6	Met	This variant is classified as Likely benign or Benign by multiple clinical testing laboratories in ClinVar (VCV000196868): 3 laboratories report Likely benign, 2 report Benign, and 1 reports Uncertain significance. The multi-laboratory consensus toward a benign interpretation, including submissions from Labcorp Genetics (Invitae), Illumina, and others, supports BP6.	clinvar
BP7	Met	This is a synonymous variant (p.Asn1784=) for which SpliceAI predicts no splice site alteration (max delta score = 0.04, well below the 0.1 threshold). No cryptic splice site creation or disruption is predicted. BP7 is met as a synonymous variant with no predicted splicing impact.	spliceai

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