Variant classification summary

NM_000110.4:c.1905+1G>A

DPYD · NP_000101.2:p.? · NM_000110.4

GRCh37: chr1:97915614 C>T · GRCh38: chr1:97450058 C>T

Gene: DPYD Transcript: NM_000110.4

Final call

Pathogenic

PVS1 very strong PS3 strong PS4 strong PM3 moderate PP3 moderate

Variant details

Gene

DPYD

Transcript

NM_000110.4

Protein

NP_000101.2:p.?

gnomAD AF

0.0050607701392873655 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong—canonical +1 splice disruption causes complete exon 14 skipping and loss of functional DPD.

2

Pathogenic: PS3 strong—direct RNA and enzyme assays demonstrate exon 14 skipping and reduced DPD activity.

3

Pathogenic: PS4 strong—exact-variant case-control odds ratio is 5.30 with a 95% confidence interval excluding 1.

4

Pathogenic: PM3 moderate—the variant occurs in trans with another disease-associated DPYD allele in affected individuals.

5

Pathogenic: PP3 moderate—SpliceAI max delta 0.993 predicts substantial splice disruption.

Final determination: Under the generic ACMG/AMP 2015 rules, one very strong criterion plus at least one strong criterion supports Pathogenic; this case has PVS1 very strong, PS3 strong, and PS4 strong, with PM3 and PP3 additional moderate evidence.

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	Met	Met, very strong: canonical +1 splice disruption causes complete exon 14 skipping and loss of functional DPD, with DPYD loss of function established as a disease mechanism.	pvs1_generic_framework PMID:10071185 PMID:12360106 PMID:23335937
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo occurrence with confirmed maternity and paternity in an affected patient.	PMID:23335937
PS3	Met	Met, strong: direct RNA analysis showed exon-14 skipping with a 165-bp deletion, and enzyme testing found reduced DPD activity in variant carriers.	PMID:10071185 PMID:12360106
PS4	Met	Met: 12/227 cases versus 2/192 controls gives OR 5.30 (95% CI 1.17–23.99), exceeding the >5.0 threshold with a confidence interval excluding 1.	PMID:23603345 PMID:10071185
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM2	Not met	Not met: gnomAD v4.1 shows AF=0.00506077, exceeding the PM2 supporting threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Met	Met: affected DPYD patients included compound heterozygous ΔEX14/C29R and multiple homozygous ΔEX14/ΔEX14 genotypes.	PMID:10071185
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo occurrence without parental confirmation is documented.	PMID:23335937
PP1	Not assessed	Not assessed: no qualifying cosegregation among multiple affected relatives is documented; the reported family has one affected homozygous index patient.	PMID:23335937 PMID:10071185
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PP3	Met	Met at moderate strength: SpliceAI max delta 0.993 meets the >=0.5 generic PP3 threshold for an intronic splice-site variant.	spliceai
PP4	Not assessed	Not assessed: the individual case phenotype or family history needed to establish a highly specific single-etiology disease presentation is unavailable.
PP5	Not met	Not met: ClinVar's exact-variant expert-panel classification is drug response, not Pathogenic or Likely pathogenic, so PP5 cannot be applied.	clinvar PMID:23335937
BA1	Not met	Not met: the highest observed all-comers allele frequency is 0.02384554, below the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: Finnish frequency is 0.02384554, but prevalence and penetrance inputs needed to establish a maximum credible frequency are unavailable.	gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: DPYD toxicity is exposure-dependent, not a disorder with established full penetrance expected at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: available studies show exon-14 skipping and reduced DPD activity, while no validated benign assay demonstrates normal splicing or enzyme function.	PMID:10071185 PMID:12360106 PMID:23335937
BS4	Not assessed	Not assessed: no affected relatives without the variant are documented, and the reported wild-type sister's disease status is unspecified.	PMID:23335937
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no qualifying cis pathogenic-variant observation or fully penetrant dominant context was reported for this target allele.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.993 is above the <=0.1 generic BP4 threshold for no predicted splice impact.	spliceai
BP5	Not assessed	Not assessed: no case-specific alternate molecular diagnosis is documented for a patient carrying this variant.
BP6	Not met	Not met: the exact-variant ClinVar expert-panel classification is drug response, not Benign or Likely benign, so BP6 cannot be applied.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules

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