Classification rationale

BP4 VUS

PPM1D c.1260+4T>C unknown · exon 5i

BP4 (Supporting): SpliceAI max delta 0.01 is below the <0.1 benign-supporting threshold. With only this single supporting benign criterion, no ACMG/AMP combination for Benign or Likely Benign is reached, and no pathogenic-direction criteria are met; the variant is classified as Uncertain Significance (VUS).

BP4 → VUS

Gene diagram · NM_003620.3 · variants mapped to exon structure

PPM1D NM_003620.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.01 is below the BP4 supporting threshold of <0.1.

SpliceAI Lookup (NM_003620.3:c.1260+4T>C, hg37): max delta score = 0.01, below the BP4 supporting threshold of <0.1 defined in the lab's generic in-silico calibration rule for intronic/non-canonical-splice-position variants (generic_acmg_classification_rules.md).REVEL and BayesDel were not applicable since this is not a missense variant; in any case BayesDel has no verified published threshold available to this pipeline and would be treated as not_available regardless of variant type.

spliceai ↗

Assessed · not applied · 6 not met · 13 not assessed

Pathogenic

PVS1 Not met: intronic +4 change sits outside the canonical splice donor, and SpliceAI max delta 0.01 predicts no splicing disruption.

PS2 Not assessed: no proband or parental testing data were available to establish de novo status.

PS3 Not assessed: no functional assay data (e.g., splicing minigene or enzymatic activity) were available for this variant.

PS4 Not assessed: no case-series or case-control enrichment data were available; the single ClinVar record is an uncertain-significance assertion.

PM2 Not met: present in population databases (51/1,613,914 alleles in gnomAD v4.1), so not absent from controls.

PM3 Not assessed: no affected-proband observations, second allele, phase, or segregation data establishing a recessive genotype.

PM6 Not assessed: no evidence of a presumed de novo occurrence without parental confirmation.

PP1 Not assessed: no affected relatives or segregation data were documented.

PP3 Not met: SpliceAI max delta 0.01 is well below the PP3 supporting threshold of >0.2.

PP4 Not assessed: no patient phenotype or disease-specific clinical features were supplied.

PP5 Not met: the exact-variant ClinVar record is uncertain significance from a single submitter, with no expert-panel classification.

Benign

BA1 Not met: allele frequency 0.00316% (51/1,613,914 alleles in gnomAD v4.1) is far below the 5% stand-alone benign threshold.

BS1 Not assessed: no disease-specific prevalence or maximum credible allele-frequency threshold was available to test against.

BS2 Not assessed: zero homozygotes observed, but carrier health status and phenotypes are not established.

BS3 Not assessed: no functional assay evidence demonstrating no damaging effect on splicing or protein function was available.

BS4 Not assessed: no unaffected relatives tested for absence of the variant were reported.

BP2 Not assessed: no observation of the variant in cis with a pathogenic variant or phase information was available.

BP5 Not assessed: no molecularly confirmed alternate genetic etiology was documented.

BP6 Not met: ClinVar classification is uncertain significance from a single laboratory, with no expert-panel benign classification.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.16002e-05; MAF= 0.00316%, 51/1613914 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000526998; MAF= 0.05270%, 48/91082 alleles, homozygotes = 0); grpmax FAF= 0.000408.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.99077e-05; MAF= 0.00399%, 10/250578 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000294137; MAF= 0.02941%, 9/30598 alleles, homozygotes = 0); grpmax FAF= 0.00015263.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0032% · 51 / 1,613,914
0 hom · FAF 0.041%

South Asian 48 / 91,082	0.053%
Remaining individuals 3 / 62,496	0.0048%

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

gnomAD v2.1

0.004% · 10 / 250,578
0 hom · FAF 0.015%

South Asian 9 / 30,598	0.029%
Remaining individuals 1 / 6,116	0.016%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2051074)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 2 PMIDs not cited in assessment

17576681 ↗ Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. CLINVAR

9536098 ↗ Statistical features of human exons and their flanking regions. CLINVAR