Variant classification summary

NM_000777.5:c.219-237A>G

CYP3A5 · NP_000768.1:p.? · NM_000777.5

GRCh37: chr7:99270539 C>C · GRCh38: chr7:99672916 T>C

Gene: CYP3A5 Transcript: NM_000777.5

Final call

Benign

PS3 strong BA1 stand-alone benign BS1 strong BP4 supporting

Variant details

Gene

CYP3A5

Transcript

NM_000777.5

Protein

NP_000768.1:p.?

gnomAD AF

0.8816064542628911 (v4.1)

ClinVar

association

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: independent studies demonstrated abnormal splicing and markedly reduced CYP3A5 expression and activity.

2

BA1 stand-alone benign: gnomAD v4.1 filtering grpmax FAF 0.931362 exceeds the 0.05 threshold.

3

BS1 strong: gnomAD v4.1 filtering grpmax FAF 0.931362 greatly exceeds the 0.01 threshold.

4

BP4 supporting: SpliceAI max delta 0.00 supports no predicted splice impact under the generic threshold.

Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as Benign because BA1 alone is sufficient, while the additional BS1 strong and BP4 supporting evidence reinforces the benign call.

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	N/A	Not applicable: c.219-237A>G is a noncanonical intronic SNV, outside generic PVS1's listed nonsense, frameshift, canonical ±1/2, initiation-codon, and exon-deletion variants.	PMID:15492926
PS1	N/A	Not applicable: c.219-237A>G is intronic and has no protein-level amino-acid change to evaluate.
PS2	Not assessed	Not assessed: no proband diagnosis, parental maternity/paternity testing, or family-history data are documented.
PS3	Met	Met, strong: independent studies linked the variant to abnormal splicing, absent or reduced CYP3A5, and 18-fold lower catalytic activity in 3/3 kidneys (P = 0.0137).	PMID:11740341 PMID:12754175
PS4	Not met	Not met: the exact-variant literature reports population frequencies but no affected-versus-control comparison, OR/RR, or confidence interval meeting the PS4 requirement.	PMID:15492926 gnomad_v4
PM1	N/A	Not applicable: the intronic variant has no protein residue that can be evaluated for hotspot or critical-domain location.
PM2	Not met	Not met: gnomAD v4.1 shows AF 0.881606 from 1,150,440 of 1,304,936 alleles, far above the <=0.0001 PM2 threshold.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no parent/offspring phase data or affected-proband observation documents this variant in trans with a pathogenic allele.	clinvar PMID:15492926
PM4	N/A	Not applicable: c.219-237A>G is an intronic SNV with p.?, not an in-frame insertion/deletion or a stop-loss variant.
PM5	N/A	Not applicable: c.219-237A>G is intronic, so no amino-acid residue exists for a different pathogenic missense comparison.
PM6	Not assessed	Not assessed: no assumed de novo occurrence or parental testing results are documented.
PP1	Not assessed	Not assessed: no affected family members, meioses, or variant-specific segregation data are documented.	PMID:15492926
PP2	N/A	Not applicable: PP2 requires a missense variant, whereas c.219-237A>G is intronic.
PP3	Not met	Not met: intronic-variant SpliceAI max delta 0.00 is below the >=0.2 PP3 supporting threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or family history is supplied to establish a highly specific presentation for a single-gene disease.	clinvar
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic classification; its record reports association, risk factor, and drug response.	clinvar
BA1	Met	Met, stand-alone: gnomAD v4.1 grpmax FAF 0.931362 exceeds the BA1 threshold of 0.05, with a qualifying large population represented.	gnomad_v4 clinvar
BS1	Met	Met, strong: gnomAD v4.1 grpmax FAF 0.931362 is far above the generic BS1 threshold of 0.01 and is not a small-isolate-only signal.	gnomad_v4 clinvar
BS2	Not assessed	Not assessed: gnomAD reports 522,108 homozygotes, but no fully penetrant early-onset disorder model or individual healthy-adult observation is established.	gnomad_v4 clinvar
BS3	Not assessed	Not assessed: reviewed assays showed reduced CYP3A5 expression and activity, but no well-established experiment demonstrated no damaging effect on protein function or splicing.	PMID:11740341 PMID:12754175
BS4	Not assessed	Not assessed: no affected relatives with documented absence of the variant are reported.	PMID:15492926
BP1	N/A	Not applicable: BP1 requires a missense variant, whereas c.219-237A>G is intronic.
BP2	Not assessed	Not assessed: no documented cis/trans relationship with a pathogenic variant is available for this intronic CYP3A5 variant.	clinvar PMID:15492926
BP3	N/A	Not applicable: c.219-237A>G is an intronic SNV, not an in-frame deletion or insertion in a repetitive region without known function.
BP4	Met	Met, supporting: intronic-variant SpliceAI max delta 0.00 meets the <=0.1 BP4 supporting threshold.	spliceai
BP5	Not assessed	Not assessed: no disease case with an independently established alternate molecular basis is documented in the available evidence.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign classification or likely benign assertion for this variant.	clinvar
BP7	N/A	Not applicable: NM_000777.5:c.219-237A>G is intronic, whereas BP7 applies only to synonymous variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.