About MBD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MBD4 c.1024T>C, p.(Ser342Pro)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant has an allele frequency far exceeding 1% in gnomAD. v2.1 total AF=2.57% (7258/282704 alleles, 413 homozygotes), v4.1 total AF=1.47% (23658/1614052 alleles, 1294 homozygotes), with a grpmax filtering AF of 12.07% in the African/African American population (v2.1) and 12.45% (v4.1). This frequency is incompatible with a rare Mendelian disease-causing variant.
BS1Strong
BS1 · strong
This variant has an allele frequency far exceeding 0.3% in gnomAD. v2.1 total AF=2.57%, v4.1 total AF=1.47%. This population frequency is greater than expected for a rare disease-causing variant. Note: the frequency evidence is also captured at the higher BA1 threshold.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no significant impact. REVEL score is 0.285 (predicts benign), BayesDel score is -0.438 (predicts benign), and SpliceAI delta score is 0.03 (predicts no splicing impact). Three independent in silico tools concordantly predict a benign effect.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
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
23,658 / 1,614,052 alleles
gnomAD v4.1: 23,658 / 1,614,052 alleles. Recorded AF 0.0146575. Recorded homozygote count 1294.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0256735; MAF= 2.56735%, 7258/282704 alleles, homozygotes = 413) and has highest observed frequency in the African/African American population (AF= 0.124048; MAF= 12.40478%, 3094/24942 alleles, homozygotes = 197); grpmax FAF= 0.120667.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.01992399565689468, 367/18420 alleles, homozygotes = 19).
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
5 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105073110, n = 1 times).
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.
29 criteria with recorded statuses: 3 met · 16 not met · 5 not assessed · 5 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.1024T>C (p.Ser342Pro) in MBD4 is classified as Benign.
This variant has an allele frequency of 2.57% in gnomAD v2.1 (7258/282704 alleles, 413 homozygotes) and 1.47% in gnomAD v4.1 (23658/1614052 alleles, 1294 homozygotes), exceeding the stand-alone benign BA1 threshold of >1% (non-VCEP). The grpmax filtering AF is 12.07% in the African/African American population (v2.1).
This variant has been reported in ClinVar as Benign by five clinical laboratories (ClinVar variation ID 1268570).
Multiple in silico tools predict a benign effect: REVEL score 0.285, BayesDel score -0.438, SpliceAI max delta score 0.03 (BP4 supporting).
No functional studies, segregation data, or de novo observations are available for this variant. No publications specifically mention NM_001276270.2:c.1024T>C.
PVS1 is not applicable as this is a missense variant, not a null variant.
No criteria match.
Met · 3
BA1 Stand aloneThis variant has an allele frequency far exceeding 1% in gnomAD. v2.1 total AF=2.57% (7258/282704 alleles, 413 homozygotes), v4.1 total AF=1.47% (23658/1614052 alleles, 1294 homozygotes), with a grpmax filtering AF of 12.07% in the African/African American population (v2.1) and 12.45% (v4.1). This frequency is incompatible with a rare Mendelian disease-causing variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=2.57%
- 413 homozygotes
- grpmax FAF=12.07% (AFR)
- v4.1 AF=1.47%
- 1294 homozygotes
- grpmax FAF=12.45% (AFR).
Sources
BS1 StrongThis variant has an allele frequency far exceeding 0.3% in gnomAD. v2.1 total AF=2.57%, v4.1 total AF=1.47%. This population frequency is greater than expected for a rare disease-causing variant. Note: the frequency evidence is also captured at the higher BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=2.57%
- v4.1 AF=1.47%. Both exceed the 0.3% BS1 threshold.
Sources
BP4 SupportingMultiple lines of computational evidence predict no significant impact. REVEL score is 0.285 (predicts benign), BayesDel score is -0.438 (predicts benign), and SpliceAI delta score is 0.03 (predicts no splicing impact). Three independent in silico tools concordantly predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.285 (benign)
- BayesDel=-0.438 (benign)
- SpliceAI max delta=0.03 (no splicing impact). Concordant benign prediction across three independent tools.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 342 resulting in the same amino acid substitution (p.Ser342Pro) has been reported as pathogenic. No PS1-eligible comparator was identified. Details ▾Hide ▴
Still missing
- No known pathogenic variant produces the same amino acid change from a different nucleotide substitution.
PS2 No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data are available in ClinVar submissions or the literature. Details ▾Hide ▴
Still missing
- No de novo data available.
PS3 No well-established functional studies have directly tested this variant or a systematically characterized range that includes residue 342. OncoKB found no variant-specific reviewed functional evidence. The in silico scores (REVEL=0.285, BayesDel=-0.438) are computational predictors, not experimental functional data, and do not satisfy PS3 requirements. Details ▾Hide ▴
Evidence considered
- REVEL score 0.285 predicts benign
- BayesDel score -0.438 predicts benign
- OncoKB reports no variant-specific functional evidence.
Still missing
- No experimental functional studies available for this variant or a systematically characterized range including residue 342.
Sources
PS4 This variant is common in the general population (gnomAD AF=2.57% in v2.1, 1.47% in v4.1, grpmax FAF=12.07% in AFR). Its prevalence in cases is not enriched relative to controls; population data strongly argue against pathogenicity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=2.57% (7258/282704 alleles
- 413 homozygotes)
- gnomAD v4.1 AF=1.47% (23658/1614052 alleles
- 1294 homozygotes)
- grpmax FAF=12.07% in African/African American population.
Sources
PM1 Residue S342 is not located in a known critical functional domain of MBD4. The methyl-CpG binding domain (MBD) spans approximately amino acids 82-147 and the DNA glycosylase domain spans approximately amino acids 426-580. S342 lies in the interdomain region with no established domain-level critical function. The cancerhotspots.org database does not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- Residue S342 is in the interdomain region between the MBD (aa 82-147) and glycosylase domain (aa 426-580)
- cancerhotspots.org shows residue not significant.
Still missing
- No domain-level functional characterization for the interdomain region around S342.
PM2 This variant is present at high frequency in gnomAD. v2.1 AF=2.57% and v4.1 AF=1.47% far exceed the PM2 threshold of <0.1% for non-VCEP framework. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=2.57% (7258/282704 alleles)
- gnomAD v4.1 AF=1.47% (23658/1614052 alleles). Both far exceed the 0.1% PM2 threshold.
Sources
PM5 No same-residue pathogenic comparator variants were identified. The PM5 candidate search found no ClinVar variants at codon 342 with a different missense change classified as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants.
Still missing
- No known pathogenic missense variants at codon 342.
Sources
pm5_candidates
PM6 No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data are available. Details ▾Hide ▴
Still missing
- No de novo data available.
PP2 MBD4 tolerates missense variation, as evidenced by the high population frequency of this missense variant (AF=2.57% in gnomAD v2.1, 413 homozygotes). The gene does not have a low rate of benign missense variation as required by PP2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 7258 missense alleles and 413 homozygotes indicate high tolerance of missense variation in MBD4.
Sources
PP3 Multiple lines of in silico evidence predict a benign effect. REVEL score is 0.285 (below the 0.5 threshold), BayesDel score is -0.438 (negative score predicts benign), and SpliceAI delta score is 0.03 (no predicted splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.285 (benign)
- BayesDel=-0.438 (benign)
- SpliceAI max delta=0.03 (no splicing impact).
Sources
PP5 ClinVar review status is 'criteria provided, single submitter' (1-star), not the required 3-star expert panel for PP5 application. In any case, ClinVar classifies this variant as Benign, not Pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign
- review status: 1-star (single submitter). Does not meet the 3-star expert panel threshold for PP5.
Sources
BS2 Although 413 homozygotes are observed in gnomAD v2.1 (and 1294 in v4.1), MBD4-related tumor predisposition syndrome is an adult-onset cancer predisposition disorder that does not have full penetrance expected at an early age, as required by BS2. The homozygote count is more appropriately captured by BA1 frequency-based evidence. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 413 homozygotes
- gnomAD v4.1: 1294 homozygotes. MBD4 tumor predisposition has adult onset and incomplete penetrance
- contraindicating strict BS2 application.
Sources
BS3 No well-established functional studies demonstrating no damaging effect are available for this variant. In silico predictors (REVEL=0.285, BayesDel=-0.438) provide computational evidence of benign effect but do not constitute well-established functional studies as required by BS3. Details ▾Hide ▴
Evidence considered
- REVEL=0.285
- BayesDel=-0.438. In silico scores suggest benign but are not well-established functional studies.
Still missing
- No experimental functional studies demonstrating no damaging effect.
Sources
revelbayesdel
BP1 While pathogenic germline MBD4 variants include truncating mutations, there is insufficient evidence to conclude that missense variants are never or rarely disease-causing for this gene. The literature describes primarily LOF truncating variants, but the spectrum of pathogenic missense variants has not been comprehensively established to satisfy BP1. Details ▾Hide ▴
Evidence considered
- MBD4 germline LOF causes tumor predisposition syndrome
- truncating variants (e.g.
- p.Gln73*) reported
- but insufficient evidence that missense variants are never disease-causing.
Still missing
- Incomplete characterization of the pathogenic missense spectrum in MBD4.
Sources
pvs1_gene_context
BP6 ClinVar review status is 'criteria provided, single submitter' (1-star). The PP5/BP6 framework rule requires a 3-star expert panel review status for supporting-strength application. Although 5 clinical laboratories classify this variant as Benign, the review status does not meet the 3-star threshold. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign by 5 labs
- review status: 1-star (single submitter). Does not meet the 3-star expert panel threshold for BP6.
Sources
PS5 No reputable source has reported this variant as pathogenic. ClinVar classifies it as Benign (5 clinical laboratories, variation ID 1268570). Details ▾Hide ▴
Evidence considered
- ClinVar classification: Benign by 5 clinical laboratories
- no submitter reports a pathogenic classification.
Sources
Not assessed · 5 · no assessment recorded
PP1 No segregation data are available for this variant. No family studies have been reported in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
- No co-segregation data available.
PP4 No patient phenotype or family history data are available for evaluation against a disease-specific presentation. Details ▾Hide ▴
Still missing
- No patient phenotype information available.
BS4 No segregation data are available for evaluation. No family studies with affected and unaffected members have been reported. Details ▾Hide ▴
Still missing
- No segregation data available.
BP2 No data on observation in trans with a pathogenic variant are available. No phase information is reported. Details ▾Hide ▴
Still missing
- No trans-phase data available.
BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant. No patient-level data were reviewed. Details ▾Hide ▴
Still missing
- No case-level data with alternate molecular diagnosis available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Ser342Pro), not a null variant (nonsense, frameshift, or canonical splice). The PVS1 variant assessment confirms the variant does not fall into any default null-variant bucket; generic PVS1 framework is not applicable. Details ▾Hide ▴
Evidence considered
- Missense substitution c.1024T>C results in p.Ser342Pro
- not a loss-of-function null variant.
Sources
PM3 N/APM3 is for recessive disorders (variant detected in trans with a pathogenic variant). MBD4-related tumor predisposition is an autosomal dominant disorder; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to non-repeat in-frame deletions/insertions or stop-loss variants. This is a missense substitution, not an in-frame indel or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions or insertions in a repetitive region without a known function. This is a missense substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.1024T>C, p.Ser342Pro), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MBD4
- Transcript
- NM_001276270.2
- Coding (HGVS c.)
- NM_001276270.2:c.1024T>C
- Protein (HGVS p.)
- NP_001263199.1:p.(Ser342Pro)
- GRCh38
- chr3:129436620 A>G
- GRCh37
- chr3:129155463 A>G
- ClinVar
- 1268570
- COSMIC
- COSV105073110
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
23,658 / 1,614,052 alleles
AF 0.0147 · 1294 homozygotes · FAF 0.124
gnomAD v2.1
7,258 / 282,704 alleles
AF 0.0257 · 413 homozygotes · FAF 0.121
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.015 · 23658 / 1,614,052 alleles · 1294 hom · FAF 0.12
| African/African American9494 / 75,000 | 0.13620 hom |
| South Asian9466 / 91,080 | 0.1618 hom |
| Remaining individuals1088 / 62,506 | 0.01739 hom |
| East Asian690 / 44,862 | 0.0159 hom |
| Middle Eastern63 / 6,062 | 0.012 hom |
| Admixed American539 / 60,018 | 0.0095 hom |
| European (non-Finnish)2295 / 1,179,986 | 0.00191 hom |
| European (Finnish)20 / 64,024 | 0.00031 |
| Ashkenazi Jewish3 / 29,602 | 0.0001 |
0 alternate alleles recorded in 1 other group: Amish.
gnomAD v2.1
AF 0.026 · 7258 / 282,704 alleles · 413 hom · FAF 0.12
| African/African American3094 / 24,942 | 0.12197 hom |
| South Asian3255 / 30,612 | 0.11208 hom |
| East Asian310 / 19,954 | 0.0163 hom |
| Remaining individuals82 / 7,214 | 0.0113 hom |
| Admixed American210 / 35,428 | 0.00592 hom |
| European (non-Finnish)300 / 129,070 | 0.0023 |
| European (Finnish)5 / 25,114 | 0.0002 |
| Ashkenazi Jewish2 / 10,370 | 0.00019 |
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0146575; MAF= 1.46575%, 23658/1614052 alleles, homozygotes = 1294) and has highest observed frequency in the African/African American population (AF= 0.126587; MAF= 12.65867%, 9494/75000 alleles, homozygotes = 620); grpmax FAF= 0.124457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0256735; MAF= 2.56735%, 7258/282704 alleles, homozygotes = 413) and has highest observed frequency in the African/African American population (AF= 0.124048; MAF= 12.40478%, 3094/24942 alleles, homozygotes = 197); grpmax FAF= 0.120667.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.01992399565689468, 367/18420 alleles, homozygotes = 19).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.285
- BayesDel
- -0.438
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no significant impact. REVEL score is 0.285 (predicts benign), BayesDel score is -0.438 (predicts benign), and SpliceAI delta score is 0.03 (predicts no splicing impact). Three independent in silico tools concordantly predict a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.285 (benign)
- BayesDel=-0.438 (benign)
- SpliceAI max delta=0.03 (no splicing impact). Concordant benign prediction across three independent tools.
Sources
PP3 Multiple lines of in silico evidence predict a benign effect. REVEL score is 0.285 (below the 0.5 threshold), BayesDel score is -0.438 (negative score predicts benign), and SpliceAI delta score is 0.03 (no predicted splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.285 (benign)
- BayesDel=-0.438 (benign)
- SpliceAI max delta=0.03 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.1024T>C, p.Ser342Pro), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.285. BayesDel score = -0.437821.
2 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
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP standards and guidelines for interpretation of sequence variants. The paper establishes the classification framework and does not discuss any specific MBD4 variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a framework refinement paper and does not discuss the MBD4 c.1024T>C variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
23,658 / 1,614,052 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
5 Benign
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/1268570/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-129155463-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-129436620-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-129436620-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001276270.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/MBD4/S342P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122999282
- 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= 0.0146575; MAF= 1.46575%, 23658/1614052 alleles, homozygotes = 1294) and has highest observed frequency in the African/African American population (AF= 0.126587; MAF= 12.65867%, 9494/75000 alleles, homozygotes = 620); grpmax FAF= 0.124457.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0256735; MAF= 2.56735%, 7258/282704 alleles, homozygotes = 413) and has highest observed frequency in the African/African American population (AF= 0.124048; MAF= 12.40478%, 3094/24942 alleles, homozygotes = 197); grpmax FAF= 0.120667.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.01992399565689468, 367/18420 alleles, homozygotes = 19).
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories). (ClinVarID = 1268570)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.285. BayesDel score = -0.437821.
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 previously been reported in somatic cancers (COSMIC; COSV105073110, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.