LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-25
Case ID: NM_001128425.2_c.505-4A_G_20260925_182919
Framework: ACMG/AMP 2015
Variant classification summary

NM_001128425.2:c.505-4A>G

MUTYH  · NP_001121897.1:p.?  · NM_001128425.2
GRCh37: chr1:45798510 T>C  ·  GRCh38: chr1:45332838 T>C
Gene: MUTYH Transcript: NM_001128425.2
Final call
Likely Benign
BS1 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MUTYH
Transcript
NM_001128425.2
Protein
NP_001121897.1:p.?
gnomAD AF
0.0009007602565246265 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BS1 strong: population frequency reaches 1.78% in African ancestry (grpmax FAF 1.64%), above the 1% frequency-expected-for-disorder threshold.
2
BP4 supporting: SpliceAI maximum delta 0.024 is below the 0.1 cutoff, predicting no splice effect at the intron 6 -4 acceptor position.
3
Likely Benign: one strong benign (BS1) plus one supporting benign (BP4) criterion satisfies the generic ACMG/AMP 2015 Likely Benign combination rule.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong benign criterion (BS1) plus one supporting benign criterion (BP4) satisfies the Likely Benign combination rule.
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: c.505-4A>G is a non-canonical intronic substitution four bases from the exon boundary, not a null variant, with no splice prediction or RNA evidence of an aberrant transcript.
pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context spliceai cspec final_classification_framework PMID:25741868 PMID:26467025
PS1 N/A Not applicable: c.505-4A>G is intronic with no amino-acid change (p.?), so PS1's same-amino-acid-change requirement cannot be met.
clinvar pm5_candidates
PS2 Not assessed Not assessed: zero probands and zero parental genotypes exist in the case record, so confirmed de novo occurrence cannot be established.
cspec PMID:25741868 clinvar gnomad_v4
PS3 Not met Not met: no RNA or enzyme-activity assay of c.505-4A>G exists, and none of the 13 usable ClinVar submissions reports functional evidence.
cspec clinvar PMID:25741868 PMID:26467025 pvs1_gene_context
PS4 Not met Not met: no case-control data exist and gnomAD grpmax FAF 0.0167 with 8 homozygotes is incompatible with the OR > 5.0 enrichment PS4 requires.
clinvar gnomad_v2 gnomad_v4 PMID:25741868
PM1 Not met Not met: c.505-4A>G is intronic with no amino-acid change, no MUTYH domain table exists, and no hotspot annotation places it in a functional domain.
cspec clinvar gnomad_v4 pm5_candidates
PM2 Not met Not met: gnomAD v4.1 total allele frequency 0.09% (1454 alleles; grpmax FAF 1.67%) far exceeds the 0.01% supporting threshold.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868
PM3 Not assessed Not assessed: no affected proband reported with c.505-4A>G in trans with a pathogenic MUTYH allele; only population data (gnomAD v4.1: 8 homozygotes, 0.09% AF) are available.
cspec clinvar gnomad_v4 PMID:25741868 PMID:21325953 PMID:27854360
PM4 N/A Not applicable: c.505-4A>G is an intronic single-nucleotide change with protein consequence p.?, so no in-frame indel or stop-loss protein-length change exists to score.
pvs1_variant_assessment spliceai cspec PMID:25741868
PM5 N/A Not applicable: PM5 requires a missense change at a codon with a known pathogenic substitute, and this intronic variant changes no residue (p.?).
pm5_candidates clinvar
PM6 Not assessed Not assessed: no proband and no parental genotypes are available in the case, so an assumed de novo occurrence cannot be established.
cspec PMID:25741868 clinvar gnomad_v4
PP1 Not assessed Not assessed: no pedigree, affected relatives, or countable meioses exist in the case, so co-segregation cannot be evaluated.
cspec PMID:25741868 clinvar PMID:26467025
PP2 N/A Not applicable: PP2 applies only to missense variants, and this intronic substitution produces no amino-acid change (p.?).
clinvar PMID:25452455
PP3 Not met Not met: SpliceAI max delta 0.024 is below the 0.2 supporting PP3 threshold for this intronic acceptor-region variant.
spliceai cspec
PP4 Not assessed Not assessed: no proband phenotype or family history exists in this variant-level case, and MUTYH adenomatous polyposis is not specific to a single genetic etiology.
cspec clinvar PMID:25741868 PMID:25645574 PMID:21325953 PMID:25452455
PP5 Not met Not met: the exact-variant ClinVar record has zero expert-panel submissions and a benign consensus, so no expert-panel pathogenic assertion exists to trigger PP5.
clinvar cspec PMID:23788249 PMID:27854360 PMID:25452455
BA1 Not met Not met: the highest ancestry frequency, 1.78% (gnomAD v2.1 African/African American; grpmax FAF 1.64%), is far below the 5% stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868
BS1 Met Met: highest frequency 1.78% (gnomAD v2.1 African ancestry; grpmax FAF 1.64%) exceeds the 1% strong-benign threshold.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868 PMID:25452455
BS2 Not met Not met: MAP is adult-onset (mid-50s) and incompletely penetrant, so BS2's full-penetrance-at-early-age premise fails despite 8 homozygotes in gnomAD v4.1.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868 PMID:25452455
BS3 Not met Not met: no assay of c.505-4A>G demonstrates preserved function; Pangolin splice gain 0.014 is computational, not functional, evidence.
cspec clinvar PMID:25741868 PMID:26467025
BS4 Not assessed Not assessed: no pedigree or genotyped affected relatives exist, so non-segregation within a family cannot be evaluated.
cspec PMID:25741868 clinvar PMID:26467025
BP1 N/A Not applicable: BP1 requires a missense variant in a truncating-only gene, while this variant is intronic and MUTYH has established missense pathogenic alleles.
clinvar PMID:25452455
BP2 Not assessed Not assessed: no individual documented with c.505-4A>G in cis with a pathogenic MUTYH variant; phase data absent, so the BP2 allelic test cannot be applied.
cspec clinvar gnomad_v4 PMID:25741868 PMID:21325953 PMID:27854360
BP3 N/A Not applicable: an intronic single-nucleotide substitution is not an in-frame indel in a repetitive region, so BP3's triggering variant type is absent.
pvs1_variant_assessment spliceai cspec PMID:25741868
BP4 Met Met at supporting: SpliceAI max delta 0.024 sits at or below the 0.1 BP4 threshold, predicting no splice impact.
spliceai cspec
BP5 Not assessed Not assessed: no case-level genotype data exist, so no patient with an alternate molecular basis for the polyposis phenotype could be identified or excluded.
clinvar PMID:25741868
BP6 Not met Not met: the exact-variant ClinVar benign consensus comes from 16 ordinary laboratory submissions with zero expert-panel classifications, which cannot trigger BP6.
clinvar cspec
BP7 N/A Not applicable: c.505-4A>G is an intronic splice-region variant, not synonymous, so BP7 is out of scope.
cspec
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