PRPF8c.2631G>ALikely benign

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Variant interpretation report

PRPF8 c.2631G>A, p.(Ala877=)

NM_006445.3:c.2631G>A NP_006436.3:p.(Ala877=) 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 Benign
Pipeline record: 4 Aug 2026 · version 7.0.5

Evidence considered

View criteria

Applied evidence criteria

BS1 (supporting): 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).
BS2 (supporting): 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.
BP4 (supporting): 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.
BP7 (supporting): 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.

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

BS1Supporting

BS1 · supporting

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).

BS2Supporting

BS2 · supporting

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.

BP4Supporting

BP4 · supporting

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.

BP7Supporting

BP7 · supporting

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.

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: BS1 supporting benign, BS2 supporting benign, BP4 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

4,034 / 1,614,020 alleles

gnomAD v4.1: 4,034 / 1,614,020 alleles. Recorded AF 0.00249935. Recorded homozygote count 86.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00450065; MAF= 0.45007%, 1273/282848 alleles, homozygotes = 33) and has highest observed frequency in the African/African American population (AF= 0.0468211; MAF= 4.68211%, 1168/24946 alleles, homozygotes = 32); grpmax FAF= 0.0444801.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029319144315343684, 54/18418 alleles, homozygotes = 0).

Applied · BS1, BS2 →

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

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only 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 · 16 not met · 0 not assessed · 6 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.2631G>A is a synonymous variant (p.Ala877=) in PRPF8 with SpliceAI max delta = 0.00, predicting no splicing impact, satisfying BP7.

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.

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.

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.

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

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.

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.

Met · 4

BS1 SupportingThis 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). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 overall AF=0.45% (>0.3% threshold)
1273 alleles observed
33 homozygotes
African/African American AF=4.68%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

33 homozygotes in gnomAD v2.1
86 homozygotes in gnomAD v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingMultiple 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splice impact)
synonymous variant with no amino acid change
no in silico predictors suggest a damaging effect

Sources

spliceai ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant (p.Ala877=)
SpliceAI max delta = 0.00
no predicted splice impact
no creation of novel splice site

Sources

spliceai ↗

Not met · 16 · evaluated, threshold not reached

PS2 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. Details ▾Hide ▴

Evidence considered

No de novo data in ClinVar or literature
high population frequency contradicts de novo pathogenicity

Sources

gnomad_v2 ↗gnomad_v4 ↗

PS3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00
no variant-specific functional studies identified

Still missing

No functional studies available for this specific variant

Sources

spliceai ↗

PS4 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.45%
v4.1 AF=0.25%
no case-control studies identified

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM1 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. Details ▾Hide ▴

Evidence considered

Residue not significant at cancerhotspots.org
no domain-specific functional evidence for this synonymous position

PM2 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). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=0.45% (>0.1%)
v4.1 AF=0.25% (>0.1%)

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM6 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. Details ▾Hide ▴

Evidence considered

No de novo reports in ClinVar or literature for this variant

Sources

gnomad_v2 ↗

PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴

Evidence considered

No segregation studies identified for this variant

Still missing

No family-based segregation data available

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splice impact)
no REVEL/BayesDel scores available for synonymous variant

Sources

spliceai ↗

PP4 No specific phenotypic data link this variant to disease. The variant is a common synonymous change observed in population databases at substantial frequency. Details ▾Hide ▴

Evidence considered

No phenotype-specific evidence for this variant
high population frequency

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP5 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. Details ▾Hide ▴

Evidence considered

ClinVar: Benign
3 clinical laboratories
review status: criteria provided
single submitter (1-star)
no expert panel classification

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 overall AF=0.45% (<1%)
v4.1 overall AF=0.25% (<1%)
African subpopulation AF=4.68% (subpopulation only)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 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. Details ▾Hide ▴

Evidence considered

No variant-specific functional studies demonstrating no damaging effect identified

Still missing

No functional studies have been performed on this variant

BS4 No segregation data are available showing lack of cosegregation with disease in affected families. Details ▾Hide ▴

Evidence considered

No family-based segregation or cosegregation data identified

Still missing

No segregation data available

BP2 No evidence that this variant has been observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴

Evidence considered

No trans-phase data with pathogenic variants identified

Still missing

No trans-phase observation data available

BP5 No evidence that this variant has been identified in a case with an alternative molecular basis for disease. Details ▾Hide ▴

Evidence considered

No cases with alternative molecular cause identified

BP6 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. Details ▾Hide ▴

Evidence considered

ClinVar: Benign
3 clinical laboratories
1-star review status
no expert panel classification
does not meet the 3-star threshold required for BP6

Sources

clinvar ↗

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis 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). Details ▾Hide ▴

Evidence considered

Synonymous variant (p.Ala877=)
variant_bucket=other
apply_generic_pvs1_framework=false

Sources

pvs1_generic_framework ↗

PS1 N/APS1 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
no amino acid change

PM5 N/APM5 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
no missense residue context
pm5_mode=unknown

PP2 N/APP2 applies to missense variants in genes where missense is an established disease mechanism. This is a synonymous variant, not a missense variant. Details ▾Hide ▴

Evidence considered

Synonymous variant
not a missense variant

BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This is a synonymous variant, not a missense variant. Details ▾Hide ▴

Evidence considered

Synonymous variant
BP1 applicable only to missense variants

PS5 N/APS5 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. Details ▾Hide ▴

Evidence considered

Synonymous variant
no amino acid change

Identifiers

Gene: PRPF8
Transcript: NM_006445.3
Coding (HGVS c.): NM_006445.3:c.2631G>A
Protein (HGVS p.): NP_006436.3:p.(Ala877=)
GRCh38: chr17:1675976 C>T
GRCh37: chr17:1579270 C>T
ClinVar: 321901

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 4,034 / 1,614,020 alleles AF 0.0025 · 86 homozygotes · FAF 0.0462

gnomAD v2.1 1,273 / 282,848 alleles AF 0.0045 · 33 homozygotes · FAF 0.0445

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0025 · 4034 / 1,614,020 alleles · 86 hom · FAF 0.046

African/African American3561 / 75,022	0.04784 hom
Remaining individuals183 / 62,488	0.00291 hom
Middle Eastern17 / 5,980	0.0028
Admixed American169 / 60,014	0.0028
South Asian20 / 91,064	0.000221 hom
European (non-Finnish)84 / 1,180,028	7.1e-05

0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0045 · 1273 / 282,848 alleles · 33 hom · FAF 0.044

African/African American1168 / 24,946	0.04732 hom
Admixed American76 / 35,438	0.0021
Remaining individuals11 / 7,228	0.0015
South Asian8 / 30,616	0.000261 hom
European (non-Finnish)10 / 129,178	7.7e-05

0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00249935; MAF= 0.24993%, 4034/1614020 alleles, homozygotes = 86) and has highest observed frequency in the African/African American population (AF= 0.0474661; MAF= 4.74661%, 3561/75022 alleles, homozygotes = 84); grpmax FAF= 0.0461652.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029319144315343684, 54/18418 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -193 bp

0.000

SpliceAI acceptor gainat +437 bp

0.000

SpliceAI donor lossat -264 bp

0.000

SpliceAI donor gainat +231 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 (no splice impact)
synonymous variant with no amino acid change
no in silico predictors suggest a damaging effect

Sources

spliceai ↗

Evidence considered

Synonymous variant (p.Ala877=)
SpliceAI max delta = 0.00
no predicted splice impact
no creation of novel splice site

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00 (no splice impact)
no REVEL/BayesDel scores available for synonymous variant

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

5 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015

Standards and guidelines for the interpretation of sequence variants (ACMG/AMP 2015). This is the foundational framework reference for variant classification criteria. NM_006445.3:c.2631G>A is not mentioned in this publication.
Does not name this variant
PMID 25741868 ↗
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

Describes in vivo CRISPR/Cas9 gene editing to correct retinal dystrophy in the S334ter rat model of autosomal dominant retinitis pigmentosa. This paper addresses the RHO gene (rhodopsin), not PRPF8. NM_006445.3:c.2631G>A was not identified.
Does not name this variant
PMID 26666451 ↗
Nonsyndromic Retinitis Pigmentosa Overview.

Adam MP et al. · 1993

GeneReviews overview of Nonsyndromic Retinitis Pigmentosa. This is a general disease-level reference. NM_006445.3:c.2631G>A in PRPF8 is not identified in the abstract or available metadata.
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 publication addresses the BEST1 gene exclusively. NM_006445.3:c.2631G>A in PRPF8 was not identified.
Does not name this variant
PMID 22234150 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a framework/methodology paper describing variant classification rules. NM_006445.3:c.2631G>A is not mentioned.
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 4,034 / 1,614,020 recorded alleles Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 3 Benign 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= 0.0029319144315343684, 54/18418 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321901)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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.