Classification rationale

BP4 VUS

PRPF8 c.2013A>G synonymous · exon 15

BP4 (Supporting): synonymous variant (p.Thr671=) with SpliceAI max delta 0.004, far below the 0.1 threshold, indicating no predicted splice impact. Overall: Variant of Uncertain Significance - a single supporting benign criterion matches no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

BP4 → VUS

Gene diagram · NM_006445.3 · variants mapped to exon structure

PRPF8 NM_006445.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 18 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

Met (Supporting): SpliceAI max delta 0.004 is far below the <0.1 BP4 threshold, indicating no predicted splice impact.

SpliceAI lookup (spliceai; tool publication Jaganathan et al. 2019, PMID 30661751, Cell 176:535-548) reports max_delta_score 0.004 for NM_006445.3:c.2013A>G.Governing PP3/BP4 calibration (output/generic_acmg_classification_rules.md, source basis Richards et al. 2015 PMID 25741868; SpliceAI thresholds as per SVI recommendations reflected in VCEP CSPECs, e.g. ATM, per Walker et al. 2023): for synonymous/non-missense variants SpliceAI max delta < 0.1 -> BP4 (supporting). Observed 0.004 < 0.1, so BP4 is met (supporting).Per the governing framework, exactly one mechanism is evaluated per variant and a synonymous variant is scored with SpliceAI only; the missense path (REVEL) is not applicable, and no REVEL/BayesDel/aGVGD scores are available for this variant (REVEL and BayesDel lookups found=false).

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no de novo observation with parental testing exists for this variant in any clinical source.

PS3 Not assessed: no functional assay data exist; SpliceAI (max delta 0.004) is in-silico and cannot substitute.

PS4 Not assessed: no case-control or affected-cohort frequency exists; gnomAD documents only general-population frequency.

PM2 Not met: highest subpopulation frequency (South Asian 0.284-0.320%) far exceeds the 0.1% threshold, so the variant is not rare.

PM6 Not assessed: no assumed de novo event or parental testing data exist for this variant.

PP1 Not assessed: no segregation analysis or affected-family genotype data exist for this variant.

PP3 Not met: SpliceAI max delta 0.004 is far below the >0.2 PP3 threshold; no other computational evidence supports pathogenicity.

PP4 Not assessed: no clinical case or phenotype data exist to evaluate phenotype specificity for this variant.

PP5 Not met: no expert-panel ClinVar pathogenic classification exists; the sole submission is a single-laboratory Benign label.

Benign

BA1 Not met: maximum allele frequency (South Asian 0.32%) is far below the >1% BA1 threshold.

BS1 Not met: population-maximum allele frequencies (grpmax FAF 0.256-0.269%) stay below the 0.3% threshold.

BS2 Not met: gnomAD homozygotes (4 in v4.1) do not satisfy the healthy-adult phenotype requirement.

BS3 Not assessed: no well-established functional studies exist; SpliceAI max delta 0.004 is in-silico, not a validated assay.

BS4 Not assessed: no affected-family non-segregation data exist for this variant.

BP2 Not assessed: no phase information (trans or cis with a pathogenic variant) is documented for this variant.

BP5 Not assessed: no case-level data exist to evaluate an alternate molecular basis for disease.

BP6 Not met: the Benign ClinVar label comes from a single laboratory, not an expert panel, so it cannot trigger BP6.

BP7 Not met: crediting BP7 would double-count the SpliceAI prediction already used for BP4, and conservation data are absent.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00017783; MAF= 0.01778%, 287/1613898 alleles, homozygotes = 4) and has highest observed frequency in the South Asian population (AF= 0.00284409; MAF= 0.28441%, 259/91066 alleles, homozygotes = 4); grpmax FAF= 0.00255955.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000378498; MAF= 0.03785%, 107/282696 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00320094; MAF= 0.32009%, 98/30616 alleles, homozygotes = 2); grpmax FAF= 0.00268731.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.018% · 287 / 1,613,898
4 hom · FAF 0.26%

South Asian 259 / 91,066	0.28% 4 hom
Remaining individuals 14 / 62,508	0.022%
African/African American 2 / 75,020	0.0027%
Admixed American 1 / 60,012	0.0017%
European (Finnish) 1 / 63,812	0.0016%
European (non-Finnish) 10 / 1,180,030	0.00085%

+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.038% · 107 / 282,696
2 hom · FAF 0.27%

South Asian 98 / 30,616	0.32% 2 hom
Remaining individuals 3 / 7,226	0.042%
European (non-Finnish) 5 / 129,186	0.0039%
Admixed American 1 / 35,440	0.0028%

+ 4 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.011% · 2 / 18,418
0 hom · FAF 0.026%

South Asian

2 / 1,362

0.15%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 750629)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR