NM_001276270.2:c.106A>G (p.Lys36Glu) in MBD4 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1: 5/251,106 alleles, 0.0020%; v4.1: 9/1,588,936 alleles, 0.00057%), meeting PM2 at supporting strength.1 Multiple in silico tools predict a benign effect: REVEL score 0.009, BayesDel score -0.666, and SpliceAI max delta 0.00, supporting BP4 (supporting benign).2 No functional studies, segregation data, or case-control evidence specific to this variant were identified. ClinVar classifications are conflicting (2-star) and do not meet the 3-star expert panel threshold for PP5 or BP6.3 The evidence profile consists of one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in insufficient evidence to classify this variant as either pathogenic or benign. This variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.4
MBD4
Final classification
VUS
MBD4 c.106A>G · p.Lys36Glu
MBD4
NM_001276270.2:c.106A>G (p.Lys36Glu) in MBD4 is a missense variant observed at extremely low frequency in population databases (gnomAD v2.1: 5/251,106 alleles, 0.0020%; v4.1: 9/1,588,936 alleles, 0.00057%), meeting PM2 at supporting strength.
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.106A>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001276270.2 · variants mapped to exon structure
MBD4
NM_001276270.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases: gnomAD v2.1 (5/251,106 alleles, AF=0.0020%), gnomAD v4.1 (9/1,588,936 alleles, AF=0.00057%). Combined AF ~0.00076%, well below the 0.1% threshold for PM2_supporting. No homozygotes observed.
gnomAD v2.1: 5/251106 alleles (0.0020%)max sub-pop AF 0.0044% (NFE)
✓
BP4
supporting
Benign
Multiple in silico computational tools predict a benign effect: REVEL score 0.009 (well below 0.5 threshold; PMID:36413997), BayesDel score -0.666 (negative, benign-leaning), and SpliceAI max delta 0.00 (no predicted splicing impact). The concordance of benign predictions from independent tools supports BP4_supporting.
REVEL score: 0.009 (benign-leaningthreshold ≤0.5)BayesDel score: -0.666 (negative
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant producing the same amino acid change (p.Lys36Glu) was identified in ClinVar or the literature.
PS3
No functional experimental data were identified for this variant.
PS4
No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls.
PM1
Position 36 (p.Lys36Glu) is in the N-terminal region of MBD4 outside the methyl-CpG binding domain (MBD, residues ~82–147) and the DNA glycosylase domain.
PP2
No gene-level missense constraint data (z-score) or evidence that MBD4 has a low rate of benign missense variation with pathogenic missense variants as a common mechanism was identified in the evidence brief.
PP3
Multiple in silico tools predict a benign effect: REVEL score 0.009 (benign-leaning, below 0.5 threshold), BayesDel score -0.666 (negative, benign-leaning), SpliceAI max delta 0.00 (no predicted splice impact).
PP5
ClinVar review status for Variation ID 2904168 is 'criteria provided, conflicting classifications' (2 stars), which does not meet the 3-star expert panel threshold required for PP5_supporting.
Benign
BA1
Combined population frequency ~0.00076% is far below the 1% threshold for BA1.
BS1
Population frequency ~0.0020% (v2.1) and ~0.00057% (v4.1) are both far below the 0.3% threshold for BS1.
BS3
No experimental functional studies demonstrating a benign effect for this variant were identified.
BP1
MBD4 is a gene in which both truncating and missense germline variants have been associated with disease (MBD4 tumor predisposition syndrome; PMID:35460607).
BP6
ClinVar review status is 'criteria provided, conflicting classifications' (2 stars), which does not meet the 3-star expert panel threshold for BP6_supporting.
N/A · 11
PVS1 · PS2 · PM5 · PM6 · PP1 · PP4 · BS2 · BS4 · BP2 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.66417e-06; MAF= 0.00057%, 9/1588936 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.10458e-05; MAF= 0.00110%, 1/90532 alleles, homozygotes = 0); grpmax FAF= 2.97e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.99119e-05; MAF= 0.00199%, 5/251106 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.40249e-05; MAF= 0.00440%, 5/113572 alleles, homozygotes = 0); grpmax FAF= 1.687e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00057%
· 9 / 1,588,936
0 hom · FAF 0.0003%
0 hom · FAF 0.0003%
South Asian 1 / 90,532 |
0.0011% |
European (non-Finnish) 8 / 1,157,230 |
0.00069% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.002%
· 5 / 251,106
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
European (non-Finnish) 5 / 113,572 |
0.0044% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant is present in ClinVar (Variation ID: 2904168); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.009. BayesDel score = -0.665958.
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
Triaged references · 5 PMIDs not cited in assessment
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
23881473 ↗
Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
CLINVAR
31022120 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
CLINVAR