Variant classification summary

NM_003620.3:c.1260+4T>C

PPM1D · NP_003611.1:p.? · NM_003620.3

GRCh37: chr17:58734206 T>C · GRCh38: chr17:60656845 T>C

Gene: PPM1D Transcript: NM_003620.3

Final call

VUS

BP4 supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.?

gnomAD AF

3.1600196788676475e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI max delta 0.01 is below the <0.1 benign-supporting threshold.

2

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).

Final determination: Generic ACMG/AMP 2015 fallback rules: a single BP4-supporting criterion alone does not meet any Benign (1 BA1; 2 BS) or Likely Benign (1 BS+1 BP; 2 BP) combination, and no pathogenic criteria are met, so the variant is classified as Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	Not met: intronic +4 change sits outside the canonical splice donor, and SpliceAI max delta 0.01 predicts no splicing disruption.	pvs1_variant_assessment pvs1_gene_context spliceai pvs1_generic_framework
PS1	N/A	Not applicable: intronic splice-region variant with no resolved protein change (p.?) to compare against known pathogenic missense variants.
PS2	Not assessed	Not assessed: no proband or parental testing data were available to establish de novo status.
PS3	Not assessed	Not assessed: no functional assay data (e.g., splicing minigene or enzymatic activity) were available for this variant.
PS4	Not assessed	Not assessed: no case-series or case-control enrichment data were available; the single ClinVar record is an uncertain-significance assertion.
PM1	N/A	Not applicable: intronic variant with no resolved protein residue to place in a mutational hotspot or functional domain.
PM2	Not met	Not met: present in population databases (51/1,613,914 alleles in gnomAD v4.1), so not absent from controls.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observations, second allele, phase, or segregation data establishing a recessive genotype.
PM4	N/A	Not applicable: not an in-frame indel or stop-loss, and SpliceAI max delta 0.01 predicts no protein-length change.	pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: no resolved amino acid change (p.?) to compare against other pathogenic missense variants at the same codon.
PM6	Not assessed	Not assessed: no evidence of a presumed de novo occurrence without parental confirmation.
PP1	Not assessed	Not assessed: no affected relatives or segregation data were documented.
PP2	N/A	Not applicable: criterion applies to missense variants; this is an intronic splice-region variant.
PP3	Not met	Not met: SpliceAI max delta 0.01 is well below the PP3 supporting threshold of >0.2.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical features were supplied.
PP5	Not met	Not met: the exact-variant ClinVar record is uncertain significance from a single submitter, with no expert-panel classification.	clinvar
BA1	Not met	Not met: allele frequency 0.00316% (51/1,613,914 alleles in gnomAD v4.1) is far below the 5% stand-alone benign threshold.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS1	Not assessed	Not assessed: no disease-specific prevalence or maximum credible allele-frequency threshold was available to test against.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: zero homozygotes observed, but carrier health status and phenotypes are not established.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay evidence demonstrating no damaging effect on splicing or protein function was available.
BS4	Not assessed	Not assessed: no unaffected relatives tested for absence of the variant were reported.
BP1	N/A	Not applicable: criterion applies to missense variants; this variant has no resolved amino acid substitution.
BP2	Not assessed	Not assessed: no observation of the variant in cis with a pathogenic variant or phase information was available.
BP3	N/A	Not applicable: applies to in-frame indels in repetitive regions; this is an intronic splice-region substitution.	pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI max delta 0.01 is below the BP4 supporting threshold of <0.1.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no molecularly confirmed alternate genetic etiology was documented.
BP6	Not met	Not met: ClinVar classification is uncertain significance from a single laboratory, with no expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: applies to synonymous coding variants; this is an intronic variant.

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