LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-22
Case ID: NM_001040108.2_c.3280_14A_T_20260922_213009
Framework: ACMG/AMP 2015
Variant classification summary

NM_001040108.2:c.3280+14A>T

MLH3  · NP_001035197.1:p.?  · NM_001040108.2
GRCh37: chr14:75513065 T>A  ·  GRCh38: chr14:75046362 T>A
Gene: MLH3 Transcript: NM_001040108.2
Final call
Likely Benign
BS1 strong BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MLH3
Transcript
NM_001040108.2
Protein
NP_001035197.1:p.?
gnomAD AF
0.0002193343882863045 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS1 (strong) - gnomAD East Asian allele frequency 1.12% (223/19,948 alleles) and grpmax filtering AF 1.01% exceed the 0.01 threshold expected for MLH3-related disease.
2
Likely Benign: BP4 (supporting) - SpliceAI max delta 0.005 indicates no splice-altering effect, far below the 0.2 supporting cutoff.
3
Not pathogenic: no pathogenic or likely pathogenic criterion is met, and no variant-level functional, segregation, de novo, or case-enrichment evidence is available.
Final determination: Under the generic ACMG/AMP 2015 fallback rules, one strong benign criterion (BS1) plus one supporting benign criterion (BP4) yields Likely Benign.
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: this intronic substitution 14 nt from the exon junction is not a null variant, and SpliceAI max delta 0.005 predicts no splice effect.
pvs1_generic_framework spliceai pvs1_gene_context PMID:25741868
PS1 N/A Not applicable: c.3280+14A>T is intronic with predicted protein consequence p.?, so it produces no amino-acid change to match an established pathogenic variant.
PMID:25741868 final_classification_framework
PS2 Not assessed Not assessed: no proband or parental genotype data was available, so a confirmed de novo occurrence could not be evaluated.
clinvar PMID:25741868 PMID:34043773
PS3 Not assessed Not assessed: no functional assay of MLH3 c.3280+14A>T exists; the only nearby data, SpliceAI max delta 0.005, is in-silico and not assay evidence.
clinvar spliceai PMID:25741868
PS4 Not met Not met: no case-control or case-enrichment data exist for c.3280+14A>T, and no MLH3 VCEP defines a numeric PS4 threshold.
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:20301390 PMID:26389258 PMID:26389505 PMID:34043773 PMID:28492532
PM1 Not met Not met: c.3280+14A>T is intronic (p.?) and outside every MLH3 critical-domain entry, with the VCEP domain table empty and SpliceAI max delta 0.005 excluding a splice hotspot.
PMID:25741868 spliceai final_classification_framework clinvar
PM2 Not met Not met: gnomAD v2.1 AF 0.0796% (225/282,678 alleles, 3 homozygotes) is about 8-fold above the 0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 PMID:25741868 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no affected-proband genotype, second MLH3 variant, or phase data exists to show c.3280+14A>T in trans with a pathogenic allele.
final_classification_framework PMID:25741868 pvs1_gene_context
PM4 N/A Not applicable: c.3280+14A>T is intronic with predicted protein NP_001035197.1:p.?, so there is no in-frame indel or stop-loss protein-length change.
pvs1_variant_assessment spliceai PMID:25741868
PM5 N/A Not applicable: c.3280+14A>T alters no codon (p.?) and zero same-residue comparator candidates were identified, so no pathogenic missense at the same residue can exist.
pm5_candidates PMID:25741868 clinvar
PM6 Not assessed Not assessed: no proband-level clinical or genotype record exists, so an assumed de novo occurrence could not be evaluated.
clinvar PMID:25741868 PMID:34043773
PP1 Not assessed Not assessed: no pedigree or affected-relative genotypes exist, so co-segregation with disease could not be evaluated across any meioses.
clinvar PMID:25741868 PMID:34043773
PP2 N/A Not applicable: c.3280+14A>T is intronic with no amino-acid substitution (p.?), failing PP2's missense-only requirement, and no MLH3 missense constraint score exists.
PMID:25741868 pvs1_gene_context
PP3 Not met Not met: SpliceAI max delta 0.005, far below the >=0.2 PP3 supporting cutoff.
spliceai PMID:25741868
PP4 Not assessed Not assessed: no proband phenotype or family history is available in this case, so PP4 specificity cannot be evaluated.
clinvar PMID:25741868 PMID:34043773
PP5 Not met Not met: none of the four ClinVar submitters is an expert panel; zero expert-panel classifications exist for c.3280+14A>T.
clinvar PMID:25741868 PMID:28492532
BA1 Not met Not met: the highest credible population frequency is 1.12% (East Asian, gnomAD v2.1), about 4.5-fold below the 5% BA1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868 generic_acmg_combination_rules
BS1 Met Met at strong: East Asian AF 1.12% (223/19,948 alleles, gnomAD v2.1) and v2.1 grpmax FAF 1.01% exceed the 0.01 BS1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868 PMID:34043773 generic_acmg_combination_rules
BS2 Not met Not met: MLH3-related disease is adult-onset and incompletely penetrant, not the fully penetrant early-onset disorder BS2 requires, despite 3 homozygotes in gnomAD.
gnomad_v2 gnomad_v4 oncokb PMID:34043773 PMID:25741868 generic_acmg_combination_rules
BS3 Not assessed Not assessed: no functional assay reports either effect for MLH3 c.3280+14A>T; SpliceAI delta 0.005 is in-silico, not assay, evidence.
clinvar spliceai PMID:25741868
BS4 Not assessed Not assessed: no affected relative genotypes exist, so lack of co-segregation in a family could not be evaluated.
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:34043773
BP1 N/A Not applicable: BP1 is limited to missense variants, and c.3280+14A>T is intronic with no amino-acid substitution (p.?).
PMID:25741868 PMID:34043773 pvs1_gene_context
BP2 Not assessed Not assessed: no pathogenic comparator variant and no cis/trans phase determination exist, so neither BP2 clause can be evaluated for c.3280+14A>T.
final_classification_framework PMID:25741868 pvs1_gene_context
BP3 N/A Not applicable: c.3280+14A>T is a single intronic substitution, not an in-frame indel in a repeat region, with SpliceAI max delta 0.005.
pvs1_variant_assessment spliceai PMID:25741868
BP4 Met Met at supporting: SpliceAI max delta 0.005, at or below the <=0.1 BP4 threshold.
spliceai PMID:25741868
BP5 Not assessed Not assessed: no case-level data on an alternate molecular basis exists, and no MLH3 VCEP defines a numeric BP5 threshold.
clinvar PMID:25741868 PMID:34043773
BP6 Not met Not met: no ClinVar expert-panel Benign or Likely benign classification exists for c.3280+14A>T; all four submitters are ordinary laboratories.
clinvar PMID:25741868 PMID:28492532
BP7 N/A Not applicable: BP7 covers only synonymous variants and c.3280+14A>T is a deep intronic change.
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.