NM_003925.3:c.1177T>G (p.Phe393Val) in MBD4 is a rare missense variant absent from gnomAD v2.1 and observed as a single heterozygous allele in gnomAD v4.1 (1/1,613,932; AF=0.000062%), meeting PM2 at supporting level.1 Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.174 (tolerated), BayesDel score −0.216 (benign), and SpliceAI max delta 0.00 (no splicing impact), meeting BP4 at supporting benign level.2 MBD4-associated disease is driven primarily by loss-of-function (truncating) variants. This missense variant occurs in a gene for which the predominant pathogenic mechanism is truncation, meeting BP1 at supporting benign level.3 Two clinically validated in silico prediction algorithms (BayesDel, REVEL) plus a splicing predictor (SpliceAI) all return results inconsistent with pathogenicity, further supporting BP4.4
MBD4
Final classification
Likely Benign
MBD4 c.1177T>G · p.Phe393Val
MBD4
NM_003925.3:c.1177T>G (p.Phe393Val) in MBD4 is a rare missense variant absent from gnomAD v2.1 and observed as a single heterozygous allele in gnomAD v4.1 (1/1,613,932; AF=0.000062%), meeting PM2 at supporting level.
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, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
MBD4 c.1177T>G
PM2 + BP1 + BP4
→
Likely Benign
Gene diagram
· NM_003925.3 · variants mapped to exon structure
MBD4
NM_003925.3
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19605e-07; MAF= 0.00006%, 1/1613932 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47448e-07; MAF= 0.00008%, 1/1180014 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
6.2e-05%
· 1 / 1,613,932
0 hom
0 hom
European (non-Finnish) 1 / 1,180,014 |
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3870863)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.174. BayesDel score = -0.216133.
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
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
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
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
31022120 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
CLINVAR