NM_003925.3:c.89C>T (p.Pro30Leu) in MBD4 is a missense variant with no ClinVar classification and no variant-specific functional data.1 The variant is extremely rare in population databases (gnomAD v4.1: 1/1,593,284 alleles, AF = 6.28 × 10⁻⁷), satisfying PM2 at supporting strength.2 Multiple concordant computational predictors (REVEL 0.016, BayesDel −0.65999, SpliceAI 0.00) predict a benign effect, satisfying BP4 at supporting_benign strength.3 PM2 (supporting pathogenic) and BP4 (supporting benign) represent equal-weight opposing evidence; under generic ACMG/AMP 2015 rules (PMID:25741868), this results in a Variant of Uncertain Significance (VUS).4 No variant-specific publications, functional studies, de novo reports, segregation data, or external classifications were identified to further inform interpretation.
MBD4
Final classification
VUS
MBD4 c.89C>T · p.Pro30Leu
MBD4
NM_003925.3:c.89C>T (p.Pro30Leu) in MBD4 is a missense variant with no ClinVar classification and no variant-specific functional data.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MBD4 c.89C>T
PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_003925.3 · variants mapped to exon structure
MBD4
NM_003925.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. gnomAD v4.1 reports a single heterozygous allele among 1,593,284 total alleles (allele frequency = 6.28 × 10⁻⁷, or 0.000063%), which is well below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada.
gnomAD v4.1: 1/1593284 alleles (AF = 6.28e-07)
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.016 (strongly benign-predicting), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico tools concordantly predict a benign effect.
REVEL: 0.016 (benign-predictingthreshold >0.5 for damaging).BayesDel: −0.65999 (benign-predicting
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 30 resulting in the same amino acid change (Pro30Leu) classified as pathogenic in ClinVar or the literature.
PS2
No de novo reports with confirmed paternity and maternity identified for this variant.
PS3
No well-established in vitro or in vivo functional studies identified for this variant.
PS4
No case-control or prevalence data comparing affected individuals to controls available for this variant.
PM1
This variant (p.Pro30Leu) is not located in a statistically significant mutational hotspot.
PM5
No pathogenic missense variants identified at the same amino acid residue (Pro30) for comparison.
PM6
No assumed de novo reports without confirmation of paternity and maternity identified for this variant.
PP1
No co-segregation data available for this variant in affected families.
PP2
Insufficient data to assess whether MBD4 has a low rate of benign missense variation.
PP3
Multiple lines of computational evidence support a benign effect.
PP4
No patient phenotype or family history data specific to this case are available for review.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
Allele frequency is far below the 1% BA1 threshold (non-VCEP).
BS1
Allele frequency is far below the 0.3% BS1 threshold (non-VCEP).
BS2
No data available regarding observation of this variant in healthy adults for a disorder with full penetrance expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant.
BS4
No non-segregation data available for this variant in affected families.
BP1
Although truncating MBD4 variants have been reported as pathogenic (e.g., c.217C>T/p.Gln73* in PMID:31322271), there is insufficient evidence that missense variants in MBD4 are not a disease mechanism.
BP2
No data on observation of this variant in trans with a pathogenic variant (recessive disorders) or in cis with a pathogenic variant (any inheritance).
BP5
No data on an alternate molecular basis for disease in a case harboring this variant.
BP6
No reputable source has classified this variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.27634e-07; MAF= 0.00006%, 1/1593284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54609e-07; MAF= 0.00009%, 1/1170126 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.3e-05%
· 1 / 1,593,284
0 hom
0 hom
European (non-Finnish) 1 / 1,170,126 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.016. BayesDel score = -0.65999.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MBD4, a DNA glycosylase, is infrequently altered in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links