PRPF8c.5352C>TLikely benign

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Variant interpretation report

PRPF8 c.5352C>T, p.(Asn1784=)

NM_006445.3:c.5352C>T NP_006436.3:p.(Asn1784=) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PRPF8

No gene-level summary was recorded for this case.

Key facts

Evidence used: 4 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Likely benign · 2 Benign · 1 Uncertain significance
Pipeline record: 29 Jun 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

BS2 (supporting): 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.
BP4 (supporting): 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.
BP6 (supporting): 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.
BP7 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 4

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 4

BS2Supporting

BS2 · supporting

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.

BP4Supporting

BP4 · supporting

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.

BP6Supporting

BP6 · supporting

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.

BP7Supporting

BP7 · supporting

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.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS2 supporting benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 4 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

2,706 / 1,613,276 alleles

gnomAD v4.1: 2,706 / 1,613,276 alleles. Recorded AF 0.00167733. Recorded homozygote count 5.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000890925; MAF= 0.08909%, 252/282852 alleles, homozygotes = 2) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00163366; MAF= 0.16337%, 211/129158 alleles, homozygotes = 1); grpmax FAF= 0.00149259.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0008142438388882857, 15/18422 alleles, homozygotes = 0).

Applied · BS2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

6 reported laboratory submissions

3 Likely benign · 2 Benign · 1 Uncertain significance.

Applied · BP6 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 5 not met · 10 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

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

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).

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).

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).

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.

Met · 4

BS2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 2 homozygotes across 282
852 alleles
gnomAD v4.1: 5 homozygotes across 1
613
276 alleles

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.04 — no predicted splicing impact
Synonymous change with no amino acid alteration

Sources

spliceai ↗

BP6 SupportingThis 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. Details ▾Hide ▴

Evidence considered

ClinVar: Likely benign (3 labs)
Benign (2 labs)
VUS (1 lab)
Labcorp/Invitae (SCV001096546): Benign
criteria provided

Sources

clinvar ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant p.(Asn1784=)
SpliceAI max delta 0.04 — no predicted splice impact

Sources

spliceai ↗

Not met · 5 · evaluated, threshold not reached

PM2 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF 0.089%
grpmax FAF 0.149%
2 homozygotes
gnomAD v4.1: AF 0.168%
grpmax FAF 0.206%
5 homozygotes

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.04 — no predicted splice impact
REVEL/BayesDel/HCI prior unavailable for synonymous variant

Sources

spliceai ↗

PP5 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. Details ▾Hide ▴

Evidence considered

ClinVar classification: Likely benign / Benign (3 LB
2 B
1 VUS)

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max subpop AF (NFE): 0.213% — below 1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 max subpop AF (NFE): 0.213% — below 0.3% BS1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo data with confirmed paternity and maternity were identified for this variant. Details ▾Hide ▴

Still missing

No trio or family-based de novo studies available

PS3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.04 — no predicted functional impact

Still missing

No in vitro or in vivo functional studies for this variant

Sources

spliceai ↗

PS4 No case-control data comparing variant prevalence in PRPF8-related disease cases versus controls were identified. Details ▾Hide ▴

Still missing

No case-control or enriched cohort data available

PM6 No de novo data (without confirmation of paternity and maternity) were identified for this variant. Details ▾Hide ▴

Still missing

No de novo observations reported

PP1 No segregation data were identified for this variant in affected families. Details ▾Hide ▴

Still missing

No segregation or co-segregation data available

PP4 No proband phenotype or clinical data were available to evaluate whether the patient's presentation is highly specific for PRPF8-related disease. Details ▾Hide ▴

Still missing

No patient phenotype data available

BS3 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. Details ▾Hide ▴

Evidence considered

SpliceAI delta 0.04 — computational prediction
not a functional study

Still missing

No variant-specific functional studies demonstrating no effect

Sources

spliceai ↗

BS4 No segregation data were available to assess lack of segregation with disease. Details ▾Hide ▴

Still missing

No segregation data available

BP2 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. Details ▾Hide ▴

Still missing

No phasing data available

BP5 No data were identified showing this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No alternate molecular basis data available

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_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. Details ▾Hide ▴

Evidence considered

Synonymous variant with no predicted null effect
SpliceAI max delta 0.04

Sources

pvs1_generic_framework ↗spliceai ↗

PS1 N/AThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
no amino acid change

PM1 N/AThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
PM1 applies to missense variants in functional domains

PM5 N/AThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
PM5 requires missense at same residue as known pathogenic missense

PP2 N/AThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
PP2 is for missense variants in constrained genes

BP1 N/AThis is a synonymous variant. BP1 is designed for missense variants in genes where truncating variants are the primary pathogenic mechanism. Details ▾Hide ▴

Evidence considered

Synonymous variant
BP1 applies to missense variants

PS5 N/APS5 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. Details ▾Hide ▴

Evidence considered

PS5 absent from generic ACMG/AMP 2015 criteria set

Sources

generic_acmg_combination_rules

Identifiers

Gene: PRPF8
Transcript: NM_006445.3
Coding (HGVS c.): NM_006445.3:c.5352C>T
Protein (HGVS p.): NP_006436.3:p.(Asn1784=)
GRCh38: chr17:1658550 G>A
GRCh37: chr17:1561844 G>A
ClinVar: 196868

Gene diagram

Every interpreted variant in PRPF8, mapped onto the exon structure of NM_006445.3. Select a row to find it on the plot.

PRPF8NM_006445.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PRPF8 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 2,706 / 1,613,276 alleles AF 0.00168 · 5 homozygotes · FAF 0.00206

gnomAD v2.1 252 / 282,852 alleles AF 0.000891 · 2 homozygotes · FAF 0.00149

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0017 · 2706 / 1,613,276 alleles · 5 hom · FAF 0.0021

European (non-Finnish)2514 / 1,179,216	0.00213 hom
Middle Eastern9 / 6,058	0.0015
Remaining individuals61 / 62,474	0.00098
South Asian64 / 91,068	0.00071 hom
African/African American35 / 75,026	0.000471 hom
Admixed American10 / 60,026	0.00017
European (Finnish)8 / 64,022	0.00012
East Asian5 / 44,872	0.00011

0 alternate alleles recorded in 2 other groups: Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00089 · 252 / 282,852 alleles · 2 hom · FAF 0.0015

European (non-Finnish)211 / 129,158	0.00161 hom
South Asian24 / 30,616	0.000781 hom
Remaining individuals3 / 7,226	0.00042
African/African American6 / 24,968	0.00024
Admixed American6 / 35,440	0.00017
European (Finnish)2 / 25,124	8e-05

0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00167733; MAF= 0.16773%, 2706/1613276 alleles, homozygotes = 5) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00213192; MAF= 0.21319%, 2514/1179216 alleles, homozygotes = 3); grpmax FAF= 0.00206229.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0008142438388882857, 15/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +53 bp

0.040

SpliceAI acceptor gainat +213 bp

0.000

SpliceAI donor lossat +133 bp

0.000

SpliceAI donor gainat +47 bp

0.040

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta 0.04 — no predicted splicing impact
Synonymous change with no amino acid alteration

Sources

spliceai ↗

Evidence considered

Synonymous variant p.(Asn1784=)
SpliceAI max delta 0.04 — no predicted splice impact

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.04 — no predicted splice impact
REVEL/BayesDel/HCI prior unavailable for synonymous variant

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

Bakondi B et al. · 2016

Reports in vivo CRISPR/Cas9 gene editing targeting the S334ter mutation in the rhodopsin (RHO) gene in a rat model of autosomal dominant retinitis pigmentosa. This paper does not discuss PRPF8 or NM_006445.3:c.5352C>T.
Does not name this variant
PMID 26666451 ↗
Nonsyndromic Retinitis Pigmentosa Overview.

Adam MP et al. · 1993

GeneReviews overview of nonsyndromic retinitis pigmentosa, covering multiple RP-associated genes. No abstract or full text was available for direct variant-level confirmation. The title and scope do not indicate specific variant discussion.
Does not name this variant
PMID 20301590 ↗
Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).

Ramsden SC et al. · 2012

Clinical utility gene card for BEST1-related dystrophies (Bestrophinopathies). This paper addresses the BEST1 gene, not PRPF8, and does not mention NM_006445.3:c.5352C>T.
Does not name this variant
PMID 22234150 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Describes the Sherloc refinement of the ACMG-AMP variant classification framework. This is a methodological paper that does not discuss PRPF8 or NM_006445.3:c.5352C>T; it was cited by a ClinVar submitter (Labcorp/Invitae, SCV001096546) as the classification methodology used.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2,706 / 1,613,276 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗

ClinVar 3 Likely benign · 2 Benign · 1 Uncertain significance Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0008142438388882857, 15/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 196868)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.