PRPF8 c.3775-14del , p.?

BP4 SupportingComputational evidence suggests this intronic variant does not impact splicing. SpliceAI predicts no splice-altering effect with a maximum delta score of 0.00, indicating the variant does not create or disrupt splice acceptor or donor sites. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted acceptor gain/loss
no donor gain/loss)

Sources

BP6 SupportingThis variant has been classified as Benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory, with criteria provided in ClinVar (SCV002951453; ClinVar Variation ID: 1921408). While the detailed criteria are not publicly available for independent evaluation, the classification from an established clinical laboratory supports a benign interpretation. Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign
criteria provided
single submitter (Labcorp Genetics/Invitae)
SCV002951453

Sources

Not met · 17 · evaluated, threshold not reached

PVS1 NM_006445.3:c.3775-14del is an intronic variant located 14 bases upstream of exon 25 in intron 24. It does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants) defined by the ClinGen SVI PVS1 framework (PMC6185798). The variant does not disrupt a canonical splice site and is not predicted to cause loss of function via aberrant splicing. Details ▾Hide ▴

Evidence considered

Variant is intronic at position c.3775-14 in intron 24
Variant class is not a null variant (bucket: other)
No canonical splice consensus disruption

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗

PS2 No de novo observation reported in ClinVar or the available literature for this variant. Details ▾Hide ▴

Evidence considered

ClinVar submission (SCV002951453) does not report de novo origin

Still missing

No trio or de novo data available for this variant

Sources

PS3 No variant-specific functional studies identified. The variant is intronic and no experimental data demonstrating a damaging effect on splicing or gene product were found. Details ▾Hide ▴

Still missing

No functional studies available for this variant

PS4 No case-control or prevalence data comparing affected vs. unaffected individuals are available for this variant. Details ▾Hide ▴

Still missing

No case-control or prevalence data

PM1 This variant is not located in an established mutational hotspot or critical functional domain. Hotspot analysis found no significant residue enrichment and the exact variant is not listed as a recurrent somatic or germline hotspot. Details ▾Hide ▴

Evidence considered

Hotspot analysis: residue not significant
variant not listed

PM6 No de novo observation (with or without confirmed paternity/maternity) has been reported for this variant. Details ▾Hide ▴

Evidence considered

ClinVar submission does not report de novo origin

Still missing

No de novo data available

Sources

PP1 No co-segregation data are available for this variant. Details ▾Hide ▴

Still missing

No co-segregation or family data

PP3 No computational evidence supports a damaging effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice effect)

Sources

PP4 No patient phenotype or clinical data are available to assess whether the variant is found in individuals with a phenotype specific for PRPF8-related disease. Details ▾Hide ▴

Still missing

No clinical phenotype data available

PP5 No reputable source has classified this variant as pathogenic. ClinVar reports it as Benign (single submitter: Labcorp Genetics/Invitae). Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign (SCV002951453)

Sources

BA1 The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is far below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism by allele frequency alone. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.00241%
well below 1% BA1 threshold

Sources

BS1 The allele frequency in gnomAD v2.1 (0.00241%) and v4.1 (0.00112%) is below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.00241%
below 0.3% BS1 threshold

Sources

BS2 No homozygotes have been observed in gnomAD for this variant (hom = 0 in both v2.1 and v4.1). In the absence of homozygous observations in healthy adults, BS2 cannot be applied. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: hom = 0
gnomAD v4.1: hom = 0

Sources

BS3 No well-established functional studies demonstrating no damaging effect on splicing or gene product are available for this variant. Details ▾Hide ▴

Evidence considered

SpliceAI delta = 0.00 is computational
not experimental functional evidence

Still missing

No functional studies (e.g.
minigene splicing assay)

Sources

BS4 No non-segregation data are available for this variant. Details ▾Hide ▴

Still missing

No segregation data

BP2 No data are available on whether this variant has been observed in trans with a known pathogenic variant in a recessive disorder. PRPF8-related disease is typically autosomal dominant (retinitis pigmentosa type 13). Details ▾Hide ▴

Still missing

No data on in trans observations

BP5 No data are available indicating this variant is found in a case with an alternative molecular basis for disease. Details ▾Hide ▴

Still missing

No data on cases with alternative molecular cause

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/AVariant is intronic and does not result in an amino acid change; no protein-level comparator is possible. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is intronic and does not cause an in-frame or out-of-frame change in protein length. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AVariant is intronic with no protein consequence (p.?); no same-residue comparator missense variants can be evaluated. Details ▾Hide ▴

Evidence considered

PM5 candidates search returned no eligible comparators

Sources

pm5_candidates

PP2 N/AVariant is not a missense change; PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AVariant is intronic, not a missense change. BP1 applies only to missense variants in genes where truncating variants are a known disease mechanism. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AVariant is a single-nucleotide intronic deletion, not an in-frame insertion/deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVariant is an intronic deletion, not a synonymous (silent) variant. BP7 applies only to synonymous variants predicted not to impact splicing. Details ▾Hide ▴

No further detail was recorded.

PS5 N/AVariant is intronic; no codon or amino acid position is affected for PS5 comparison. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PRPF8
Transcript: NM_006445.3
Coding (HGVS c.): NM_006445.3:c.3775-14del
Protein (HGVS p.): NP_006436.3:p.?
GRCh38: chr17:1662166 GA>G
GRCh37: chr17:1565460 GA>G
ClinVar: 1921408
COSMIC: COSV59262866

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 18 / 1,613,790 alleles AF 1.12e-05 · 0 homozygotes · FAF 4.28e-05

gnomAD v2.1 6 / 248,886 alleles AF 2.41e-05 · 0 homozygotes · FAF 3.9e-05

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.1e-05 · 18 / 1,613,790 alleles · 0 hom · FAF 4.3e-05

Admixed American6 / 59,994	0.0001
Remaining individuals2 / 62,494	3.2e-05
European (non-Finnish)10 / 1,179,902	8.5e-06

0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 2.4e-05 · 6 / 248,886 alleles · 0 hom · FAF 3.9e-05

Admixed American4 / 34,542	0.00012
European (Finnish)1 / 21,366	4.7e-05
European (non-Finnish)1 / 112,768	8.9e-06

0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.11539e-05; MAF= 0.00112%, 18/1613790 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00010001; MAF= 0.01000%, 6/59994 alleles, homozygotes = 0); grpmax FAF= 4.284e-05.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 (no predicted acceptor gain/loss
no donor gain/loss)

Sources

Evidence considered

SpliceAI max delta = 0.00 (no predicted splice effect)

Sources