LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-02
Case ID: NM_001276270.2_c.1073T_C_20260902_164835
Framework: ACMG/AMP 2015
Variant classification summary

NM_001276270.2:c.1073T>C

MBD4  · NP_001263199.1:p.(Ile358Thr)  · NM_001276270.2
GRCh37: chr3:129155414 A>G  ·  GRCh38: chr3:129436571 A>G
Gene: MBD4 Transcript: NM_001276270.2
Final call
Benign
BA1 stand-alone benign BS1 strong benign BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MBD4
Transcript
NM_001276270.2
Protein
NP_001263199.1:p.(Ile358Thr)
gnomAD AF
0.010139216743183212 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BA1 (Stand-alone): gnomAD v4.1 allele frequency of 1.01% exceeds the 1% threshold for a rare Mendelian disorder.
2
BS1 (Strong): population frequency of 1.01% exceeds the 0.3% benign threshold.
3
BP4 (Supporting): REVEL score of 0.218 falls below the 0.250 benign cutoff.
4
BA1 alone is sufficient for a Benign classification; BS1 and BP4 are concordant but not required.
Final determination: Under generic ACMG/AMP 2015 rules, BA1 alone supports a Benign classification.
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 missense change is not one of the null variant classes (nonsense, frameshift, splice-site) that PVS1 covers.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no validated report of this same amino-acid change (p.Ile358Thr) as pathogenic was available.
clinvar PMID:25626707 PMID:23619275 PMID:23169492 PMID:25741868
PS2 Not assessed Not assessed: no de novo observation of the variant with confirmed maternity and paternity was documented.
PS3 Not assessed Not assessed: no validated functional assay evidence showing p.Ile358Thr has a damaging effect was available.
oncokb PMID:25626707 PMID:23619275 PMID:23169492 PMID:25741868
PS4 Not assessed Not assessed: no case-control or cohort data showed enrichment of this variant in affected individuals.
PMID:23169492
PM1 Not assessed Not assessed: no authoritative critical-domain or hotspot evidence covering MBD4 residue 358 was available.
oncokb
PM2 Not met Not met: gnomAD v4.1 allele frequency of 1.01% (84 homozygotes) far exceeds the <0.1% rarity threshold.
gnomad_v4 gnomad_v2 gnomad_canada
PM3 Not assessed Not assessed: no evidence showed the variant in trans with a pathogenic MBD4 variant in an affected individual.
generic_acmg_combination_rules
PM4 N/A Not applicable: this missense change does not alter protein length, which PM4 requires.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no verified pathogenic missense variant at the same residue was available for comparison.
pm5_candidates clinvar
PM6 Not assessed Not assessed: no case or literature evidence documents the variant as de novo.
PP1 Not assessed Not assessed: no family segregation data for the variant were available.
PP2 Not assessed Not assessed: no evidence established that benign missense variation is uncommon in MBD4.
pvs1_gene_context generic_acmg_combination_rules
PP3 Not met Not met: REVEL score 0.218 is below the PP3 threshold of 0.750.
revel spliceai bayesdel generic_acmg_combination_rules
PP4 Not assessed Not assessed: no phenotype or clinical context data were provided.
PP5 Not met Not met: no ClinVar expert-panel pathogenic or likely pathogenic classification exists for this exact variant.
clinvar
BA1 Met Met (stand-alone benign): gnomAD v4.1 allele frequency of 1.01% exceeds the 1% BA1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada
BS1 Met Met (strong benign): allele frequency of 1.01% exceeds the 0.3% BS1 threshold.
gnomad_v4 gnomad_v2 gnomad_canada
BS2 Not assessed Not assessed: homozygote counts in population databases alone do not establish that healthy adults were observed.
gnomad_v4 gnomad_v2 gnomad_canada
BS3 Not assessed Not assessed: no functional assay evidence showing the variant preserves normal protein function was available.
oncokb PMID:25626707 PMID:23619275 PMID:23169492 PMID:25741868
BS4 Not assessed Not assessed: no at-risk relatives were tested, so non-segregation could not be evaluated.
BP1 Not assessed Not assessed: no variant-spectrum evidence established that missense changes do not cause MBD4 disease.
pvs1_gene_context PMID:25626707 PMID:23619275 PMID:23169492 PMID:25741868
BP2 Not assessed Not assessed: no evidence placed this variant in cis or trans with another pathogenic variant.
generic_acmg_combination_rules
BP3 N/A Not applicable: this missense change is not an in-frame insertion/deletion in a repeat region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met (supporting): REVEL score 0.218 is below the BP4 benign cutoff of 0.250.
revel generic_acmg_combination_rules
BP5 Not assessed Not assessed: no evidence of an alternate cause of disease in a tested individual was provided.
BP6 Not met Not met: no ClinVar expert-panel benign or likely benign classification exists for this exact variant.
clinvar
BP7 N/A Not applicable: this missense change is not a synonymous variant, which BP7 requires.
generic_acmg_combination_rules
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