About MBD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MBD4 c.1015G>A, p.(Ala339Thr)
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
NM_003925.3:c.1015G>A is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), with allele frequency of 0% in all populations, well below the PM2 threshold of 0.1%.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
NM_003925.3:c.1015G>A is a missense variant in MBD4, a gene for which the established disease mechanism is loss-of-function via truncating variants. The known germline pathogenic variants in MBD4 are primarily nonsense and frameshift alterations (e.g., c.217C>T/p.Gln73* reported in PMID:31322271; multi-tumor syndrome described in PMID:35460607). A missense variant in a primarily truncating-disease gene warrants BP1.
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, BP1 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.270 maximum delta
Recorded SpliceAI maximum delta score: 0.270. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
29 criteria with recorded statuses: 2 met · 22 not met · 0 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_003925.3:c.1015G>A (p.Ala339Thr) is absent from all gnomAD population databases (v2.1, v4.1, Canada), meeting PM2 at supporting strength.
MBD4 germline disease is mediated by loss-of-function via truncating variants; this missense variant qualifies for BP1 (supporting benign) as missense variation is not the established pathogenic mechanism.
Computational predictors are discordant: REVEL 0.302 (weakly pathogenic-leaning), BayesDel -0.489624 (benign-leaning), SpliceAI max delta 0.27 (intermediate). Neither PP3 nor BP4 is met.
No functional studies, no case-control data, no segregation data, no de novo observations, and no ClinVar entries exist for this variant. All other criteria are not met or not applicable.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP1), the net evidence score is zero, consistent with a variant of uncertain significance (VUS) per ACMG/AMP 2015 generic classification rules.
No criteria match.
Met · 2
PM2 SupportingNM_003925.3:c.1015G>A is absent from gnomAD v2.1 (0 alleles), gnomAD v4.1 (0 alleles), and gnomAD-Canada v1.0 (0 alleles), with allele frequency of 0% in all populations, well below the PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0/0 alleles
- AF=0%)
- absent from gnomAD v4.1 (0/0 alleles
- absent from gnomAD-Canada v1.0 (0/0 alleles).
Sources
BP1 SupportingNM_003925.3:c.1015G>A is a missense variant in MBD4, a gene for which the established disease mechanism is loss-of-function via truncating variants. The known germline pathogenic variants in MBD4 are primarily nonsense and frameshift alterations (e.g., c.217C>T/p.Gln73* reported in PMID:31322271; multi-tumor syndrome described in PMID:35460607). A missense variant in a primarily truncating-disease gene warrants BP1. Details ▾Hide ▴
Evidence considered
- MBD4 germline disease mechanism is LoF via truncating variants (PMID:31322271 reports p.Gln73*
- PMID:35460607 establishes biallelic LoF as multi-tumor predisposition syndrome). Missense variants are not the established mechanism.
Sources
3132227135460607
Not met · 22 · evaluated, threshold not reached
PS1 No established pathogenic variant with the same amino acid change (Ala339Thr) has been reported in ClinVar or the literature. PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar is absent for this variant
- no pathogenic comparator with identical amino acid change identified.
Still missing
- No known pathogenic variant at this residue for comparison.
Sources
PS2 No de novo occurrence of NM_003925.3:c.1015G>A with confirmed maternity and paternity has been reported in the literature, ClinVar, or de novo databases. Details ▾Hide ▴
Evidence considered
- No de novo observations identified across literature and database searches.
Still missing
- Absence of de novo testing or reporting for this variant.
PS3 No well-established functional studies demonstrating a damaging effect of p.Ala339Thr on MBD4 glycosylase activity or protein function have been identified. In silico predictions (REVEL, BayesDel) are not a substitute for functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
- no functional studies identified in literature.
Still missing
- No in vitro or in vivo functional assays for MBD4 p.Ala339Thr.
Sources
PS4 The variant is absent from ClinVar and gnomAD, and no case-control study demonstrating statistically significant enrichment of this variant in affected individuals has been identified. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- absent from ClinVar
- no patient observations available.
Still missing
- No case counts or case-control data for this variant.
Sources
PM1 Residue Ala339 is located in the MBD4 uracil-DNA glycosylase domain, a critical functional region. However, PM1 requires evidence that the domain has a low rate of benign missense variation, which has not been established through gnomAD constraint metrics or domain-specific benign variation analysis. Details ▾Hide ▴
Evidence considered
- Ala339 lies within the uracil-DNA glycosylase domain (residues 318-580)
- domain functional significance noted but constraint data unavailable.
Still missing
- No gnomAD missense constraint metrics for the glycosylase domain
- no domain-specific benign variation rate established.
PM5 No established pathogenic missense variant at the same residue (Ala339) with a different amino acid change has been identified. The automatic PM5 candidate harvest returned zero candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants identified in ClinVar.
Still missing
- No pathogenic comparator at codon 339.
Sources
pm5_candidates
PM6 No de novo observation of NM_003925.3:c.1015G>A, with or without confirmation of maternity and paternity, has been reported. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo observations.
PP1 No segregation data are available for NM_003925.3:c.1015G>A. No family studies demonstrating co-segregation of this variant with disease have been identified. Details ▾Hide ▴
Evidence considered
- No segregation or family studies identified.
Still missing
- No segregation data
- no familial case reports.
PP2 MBD4 disease mechanism is loss-of-function via truncating variants, not missense. Known pathogenic MBD4 variants are primarily nonsense/frameshift (e.g., c.217C>T/p.Gln73*). HCI prior score is unavailable for MBD4. PP2 is not applicable to a gene where missense is not the established disease mechanism. Details ▾Hide ▴
Evidence considered
- MBD4 disease mechanism is LoF via truncating variants (PMID:31322271
- PMID:35460607)
- HCI prior not available for MBD4.
Sources
3132227135460607
PP3 In silico predictions are discordant: REVEL score is 0.302 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.489624 (benign-leaning), and SpliceAI max delta is 0.27 (intermediate). Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.302 (weakly pathogenic-leaning)
- BayesDel -0.489624 (benign-leaning)
- SpliceAI max delta 0.27 (intermediate).
Sources
PP4 No patient phenotype or family history data are available for NM_003925.3:c.1015G>A. The variant has not been observed in any clinically characterized individual. Details ▾Hide ▴
Evidence considered
- No clinically characterized cases with this variant.
Still missing
- No patient phenotype data available.
PP5 NM_003925.3:c.1015G>A has not been reported as pathogenic by a reputable clinical source. It is absent from ClinVar and has no published clinical assertions of pathogenicity. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has reported this variant as pathogenic.
Sources
BA1 NM_003925.3:c.1015G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0%, which is well below the BA1 threshold of 1%. Details ▾Hide ▴
BS1 NM_003925.3:c.1015G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0%, which is well below the BS1 threshold of 0.3%. Details ▾Hide ▴
BS2 No observation of NM_003925.3:c.1015G>A in healthy adults has been reported. BS2 requires documented observation in healthy individuals for a fully penetrant disorder, which is not available. Details ▾Hide ▴
Evidence considered
- No observation in healthy adult controls documented.
Still missing
- No healthy adult observations.
BS3 No well-established functional studies demonstrating a benign effect of p.Ala339Thr on MBD4 function have been identified. Computational predictions alone do not constitute BS3-level evidence. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating normal MBD4 activity for p.Ala339Thr.
Still missing
- No functional assays evaluating p.Ala339Thr effect.
BS4 No evidence of lack of segregation in affected families has been reported for NM_003925.3:c.1015G>A. Details ▾Hide ▴
Evidence considered
- No non-segregation data available.
Still missing
- No family segregation studies.
BP2 No observation of NM_003925.3:c.1015G>A in trans with a pathogenic variant in a fully penetrant dominant gene has been reported. BP2 is not applicable in the absence of such data. Details ▾Hide ▴
Evidence considered
- No trans observations with pathogenic variants in dominant genes.
Still missing
- No co-occurrence data with pathogenic variants in other dominant genes.
BP4 Multiple lines of computational evidence do not consistently support a benign effect. BayesDel score is -0.489624 (benign-leaning), but REVEL score is 0.302 (weakly pathogenic-leaning) and SpliceAI max delta is 0.27 (intermediate). Discordant predictions do not meet the 'multiple lines' requirement for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel -0.489624 (benign-leaning)
- REVEL 0.302 (weakly pathogenic-leaning)
- SpliceAI 0.27 (intermediate). Discordant
- only one tool supports benign.
Sources
BP5 No case has been reported in which NM_003925.3:c.1015G>A was observed in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis cases reported.
Still missing
- No cases with alternate molecular etiology.
BP6 NM_003925.3:c.1015G>A is absent from ClinVar and has not been reported as benign by a reputable clinical source. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has reported this variant as benign.
Sources
PS5 NM_003925.3:c.1015G>A has not been reported as pathogenic by a reputable source. It is absent from ClinVar and has no published clinical assertions. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has classified this variant as pathogenic.
Still missing
- No established clinical classification for this variant.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_003925.3:c.1015G>A (p.Ala339Thr) is a missense variant, not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). SpliceAI max delta score of 0.27 is below the threshold to invoke a splicing null effect per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- SpliceAI max delta 0.27 (DS_AL=0.27
- DS_AG=0.15
- DS_DG=0.0
- DS_DL=0.0)
- does not meet null-variant criteria.
Sources
PM3 N/ANo second pathogenic MBD4 variant has been identified in trans with NM_003925.3:c.1015G>A; no biallelic observation available for assessment. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANM_003925.3:c.1015G>A is a single-nucleotide substitution, not a non-frameshift indel or stop-loss variant. PM4 applies to protein-length-altering variants. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ANM_003925.3:c.1015G>A is a single-nucleotide substitution, not an in-frame insertion or deletion. BP3 applies to in-frame indels in repeat regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_003925.3:c.1015G>A is a missense variant (p.Ala339Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable.
Identifiers
- Gene
- MBD4
- Transcript
- NM_003925.3
- Coding (HGVS c.)
- NM_003925.3:c.1015G>A
- Protein (HGVS p.)
- NP_003916.1:p.(Ala339Thr)
- GRCh38
- chr3:129436629 C>T
- GRCh37
- chr3:129155472 C>T
Gene diagram
Every interpreted variant in MBD4, mapped onto the exon structure of NM_003925.3. Select a row to find it on the plot.
MBD4NM_003925.3
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.302
- BayesDel
- -0.490
How the predictions were used
PP3 In silico predictions are discordant: REVEL score is 0.302 (below the typical pathogenic threshold of 0.5), BayesDel score is -0.489624 (benign-leaning), and SpliceAI max delta is 0.27 (intermediate). Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.302 (weakly pathogenic-leaning)
- BayesDel -0.489624 (benign-leaning)
- SpliceAI max delta 0.27 (intermediate).
Sources
BP4 Multiple lines of computational evidence do not consistently support a benign effect. BayesDel score is -0.489624 (benign-leaning), but REVEL score is 0.302 (weakly pathogenic-leaning) and SpliceAI max delta is 0.27 (intermediate). Discordant predictions do not meet the 'multiple lines' requirement for BP4. Details ▾Hide ▴
Evidence considered
- BayesDel -0.489624 (benign-leaning)
- REVEL 0.302 (weakly pathogenic-leaning)
- SpliceAI 0.27 (intermediate). Discordant
- only one tool supports benign.
Sources
BP7 N/ANM_003925.3:c.1015G>A is a missense variant (p.Ala339Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 not applicable.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.302. BayesDel score = -0.489624.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.270
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/?term=NM_003925.3%3Ac.1015G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-129155472-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-129436629-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003925.3%3Ac.1015…
- OncoKB ↗www.oncokb.org/gene/MBD4/A339T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MBD4+c.1015G%3EA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.302. BayesDel score = -0.489624.
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.