About MBD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MBD4 c.106A>G, p.(Lys36Glu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,588,936 alleles
gnomAD v4.1: 9 / 1,588,936 alleles. Recorded AF 5.66417e-06. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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).
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 5/251
- 106 alleles (0.0020%)
- max sub-pop AF 0.0044% (NFE)
- 0 homozygotes
- gnomAD v4.1: 9/1
- 588
- 936 alleles (0.00057%)
- max sub-pop AF 0.0011% (SAS)
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.009 (benign-leaning
- threshold ≤0.5)
- BayesDel score: -0.666 (negative
- benign-leaning)
- SpliceAI max delta: 0.00 (no splice alteration predicted)
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No previously established pathogenic variant producing the same amino acid change (p.Lys36Glu) was identified in ClinVar or the literature. PS1 evidence is absent. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 2904168 has no submitters reporting this change as pathogenic
- two submitters classify as Likely benign and Uncertain significance.
Sources
PS3 No functional experimental data were identified for this variant. OncoKB reports unknown oncogenic effect; no literature contains functional characterization of c.106A>G (p.Lys36Glu). Domain-level inference alone does not satisfy PS3. Details ▾Hide ▴
Evidence considered
- OncoKB classifies this variant as Unknown Oncogenic Effect. No variant-specific functional studies found in the literature.
Still missing
- No experimental functional data available for p.Lys36Glu
Sources
PS4 No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls. Details ▾Hide ▴
Still missing
- No affected-individual data available for this variant
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. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. No literature establishes this N-terminal region as a critical functional domain. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant. MBD4 MBD domain spans ~aa 82–147
- position 36 lies N-terminal to this domain. No functional domain characterized at this position.
Sources
pvs1_variant_assessment
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. Details ▾Hide ▴
Evidence considered
- No missense constraint metric available for MBD4 in evidence sources.
Still missing
- Missense constraint data for MBD4 not available
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). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.009 (benign-leaning)
- BayesDel: -0.666 (benign-leaning)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
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. Two submitters report Likely benign (Ambry Genetics) and Uncertain significance (Invitae). Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 2904168: 2 submissions
- conflicting classifications (Likely benign + VUS)
- review status 2-star (criteria provided
- conflicting classifications)
Sources
BA1 Combined population frequency ~0.00076% is far below the 1% threshold for BA1. This variant is not common in the general population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0020%
- v4.1 AF=0.00057%. Both far below 1%.
Sources
BS1 Population frequency ~0.0020% (v2.1) and ~0.00057% (v4.1) are both far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- Highest sub-population AF is 0.0044% (v2.1 NFE)
- well below 0.3% BS1 threshold.
Sources
BS3 No experimental functional studies demonstrating a benign effect for this variant were identified. In silico predictions (REVEL, BayesDel) are assessed under BP4, not BS3. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies showing benign effect identified.
Still missing
- No experimental functional data available
BP1 MBD4 is a gene in which both truncating and missense germline variants have been associated with disease (MBD4 tumor predisposition syndrome; PMID:35460607). Truncating variants are not the sole disease mechanism, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- MBD4 germline deficiency syndrome includes both truncating and potential missense pathogenic variants (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. While Ambry Genetics classifies as Likely benign, the conflicting VUS classification and 2-star review status preclude BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 2904168: Ambry Genetics reports Likely benign
- Invitae reports Uncertain significance. Review status 2-star (criteria provided
- conflicting classifications).
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is a missense substitution (c.106A>G, p.Lys36Glu) and does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant. PVS1 variant assessment confirms bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PS2 N/ANo de novo occurrence data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants with established pathogenic classification were identified. PM5 candidate harvesting was unable to confirm classic same-residue semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned no same-residue pathogenic comparators for p.Lys36.
Sources
pm5_candidates
PM6 N/ANo de novo occurrence data or maternity/paternity confirmation reported for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo segregation data are available for this variant in affected families. Details ▾Hide ▴
No further detail was recorded.
PP4 N/ANo patient phenotype or clinical data specific to this variant were provided for assessment. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo data on observation of this variant in healthy adults with full penetrance expected at an early age were available. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo segregation data are available for this variant. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo data on observation in trans with a known pathogenic MBD4 variant available. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo alternate molecular basis for disease was identified to explain the phenotype independent of this variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.106A>G, p.Lys36Glu) not a synonymous or intronic variant at a position where splicing is not predicted to be altered. BP7 applies only to synonymous variants. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion defined in the standard ACMG/AMP 2015 framework used for this assessment. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MBD4
- Transcript
- NM_001276270.2
- Coding (HGVS c.)
- NM_001276270.2:c.106A>G
- Protein (HGVS p.)
- NP_001263199.1:p.(Lys36Glu)
- GRCh38
- chr3:129437949 T>C
- GRCh37
- chr3:129156792 T>C
- ClinVar
- 2904168
Gene diagram
Every interpreted variant in MBD4, mapped onto the exon structure of NM_001276270.2. Select a row to find it on the plot.
MBD4NM_001276270.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MBD4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
9 / 1,588,936 alleles
AF 5.66e-06 · 0 homozygotes · FAF 2.97e-06
gnomAD v2.1
5 / 251,106 alleles
AF 1.99e-05 · 0 homozygotes · FAF 1.69e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.7e-06 · 9 / 1,588,936 alleles · 0 hom · FAF 3e-06
| South Asian1 / 90,532 | 1.1e-05 |
| European (non-Finnish)8 / 1,157,230 | 6.9e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2e-05 · 5 / 251,106 alleles · 0 hom · FAF 1.7e-05
| European (non-Finnish)5 / 113,572 | 4.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.009
- BayesDel
- -0.666
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.009 (benign-leaning
- threshold ≤0.5)
- BayesDel score: -0.666 (negative
- benign-leaning)
- SpliceAI max delta: 0.00 (no splice alteration predicted)
Sources
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). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.009 (benign-leaning)
- BayesDel: -0.666 (benign-leaning)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP7 N/AThis is a missense variant (c.106A>G, p.Lys36Glu) not a synonymous or intronic variant at a position where splicing is not predicted to be altered. BP7 applies only to synonymous variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.009. BayesDel score = -0.665958.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015Position statement on the limited role of whole-genome sequencing in newborn screening programs. Discusses ethical, legal, and social implications of NGS technologies. MBD4 and NM_001276270.2:c.106A>G are not mentioned.Does not name this variant
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PMID 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.Edwards JG et al. · 2015Joint statement from ACMG, ACOG, NSGC, and other organizations providing guidance on expanded carrier screening in reproductive medicine. Discusses general screening principles. MBD4 and NM_001276270.2:c.106A>G are not mentioned.Does not name this variant
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PMID 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.Therrell BL et al. · 2013Recommendations on including newborn screening bloodspot collection device serial numbers on birth certificates. MBD4 and NM_001276270.2:c.106A>G are not mentioned.Does not name this variant
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PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.Blout C et al. · 2014National Society of Genetic Counselors position statement on newborn screening, education, consent, and residual blood spots. MBD4 and NM_001276270.2:c.106A>G are not mentioned.Does not name this variant
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PMID 31022120 ↗ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.ACOG Committee Opinion on newborn screening and the role of the obstetrician-gynecologist. MBD4 and NM_001276270.2:c.106A>G are not mentioned.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
9 / 1,588,936 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2904168/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-129156792-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-129437949-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-129437949-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001276270.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/MBD4/K36E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MBD4+c.106A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.