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MBD4c.89C>TUncertain significance
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Variant interpretation report

MBD4 c.89C>T, p.(Pro30Leu)

NM_003925.3:c.89C>T NP_003916.1:p.(Pro30Leu) View identifiers
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.

About MBD4

No gene-level summary was recorded for this case.

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 v4.1 reports a single heterozygous allele among 1,593,284 total alleles (allele frequency = 6.28 × 10⁻⁷, or 0.000063%), which is well below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.016 (strongly benign-predicting), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico tools concordantly predict a benign effect.

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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → 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
COSMIC ↗Cancer Hotspots ↗
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 · 4 not met · 18 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_003925.3:c.89C>T (p.Pro30Leu) in MBD4 is a missense variant with no ClinVar classification and no variant-specific functional data.

The variant is extremely rare in population databases (gnomAD v4.1: 1/1,593,284 alleles, AF = 6.28 × 10⁻⁷), satisfying PM2 at supporting strength.

Multiple concordant computational predictors (REVEL 0.016, BayesDel −0.65999, SpliceAI 0.00) predict a benign effect, satisfying BP4 at supporting_benign strength.

PM2 (supporting pathogenic) and BP4 (supporting benign) represent equal-weight opposing evidence; under generic ACMG/AMP 2015 rules (PMID:25741868), this results in a Variant of Uncertain Significance (VUS).

No variant-specific publications, functional studies, de novo reports, segregation data, or external classifications were identified to further inform interpretation.

Met · 2

PM2 SupportingThis variant is extremely rare in population databases. gnomAD v4.1 reports a single heterozygous allele among 1,593,284 total alleles (allele frequency = 6.28 × 10⁻⁷, or 0.000063%), which is well below the 0.1% PM2 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 1/1
  • 593
  • 284 alleles (AF = 6.28e-07)
  • 0 homozygotes.
  • gnomAD v2.1: absent.
  • gnomAD-Canada v1.0: absent.
Sources
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.016 (strongly benign-predicting), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico tools concordantly predict a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.016 (benign-predicting
  • threshold >0.5 for damaging).
  • BayesDel: −0.65999 (benign-predicting
  • positive scores indicate pathogenicity).
  • SpliceAI: max delta = 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 4 · evaluated, threshold not reached

PM1 This variant (p.Pro30Leu) is not located in a statistically significant mutational hotspot. Cancer Hotspots analysis found no significant hotspot at residue Pro30. The residue is in the N-terminal region of MBD4, upstream of the methyl-CpG binding domain (residues ~82-147), and there is no evidence it lies within a critical, well-established functional domain. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no significant hotspot at MBD4 P30.
  • Residue 30 is N-terminal to the MBD domain
  • no established critical functional domain at this position.
PP3 Multiple lines of computational evidence support a benign effect. REVEL score is 0.016 (well below the 0.5 threshold, predicting benign), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All available in silico predictors agree on a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.016 (benign-predicting).
  • BayesDel: −0.65999 (benign-predicting).
  • SpliceAI: max delta = 0.00 (no splice impact predicted).
Sources
revelbayesdelspliceai ↗
BA1 Allele frequency is far below the 1% BA1 threshold (non-VCEP). gnomAD v4.1 reports a single allele (AF = 6.28 × 10⁻⁷). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.28e-07
  • far below 1% threshold.
Sources
gnomad_v4 ↗
BS1 Allele frequency is far below the 0.3% BS1 threshold (non-VCEP). gnomAD v4.1 reports a single allele (AF = 6.28 × 10⁻⁷). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 6.28e-07
  • far below 0.3% threshold.
Sources
gnomad_v4 ↗

Not assessed · 18 · no assessment recorded

PS1 No evidence of a different nucleotide change at codon 30 resulting in the same amino acid change (Pro30Leu) classified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Still missing
  • No same-residue pathogenic comparator variants identified.
PS2 No de novo reports with confirmed paternity and maternity identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PS3 No well-established in vitro or in vivo functional studies identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence.
Still missing
  • No functional assay data available for p.Pro30Leu.
Sources
oncokb ↗
PS4 No case-control or prevalence data comparing affected individuals to controls available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort prevalence data.
PM5 No pathogenic missense variants identified at the same amino acid residue (Pro30) for comparison. PM5 candidate harvesting found no eligible comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: no same-residue pathogenic missense variants found.
Still missing
  • No pathogenic comparators at codon 30 identified.
Sources
pm5_candidates
PM6 No assumed de novo reports without confirmation of paternity and maternity identified for this variant. Details ▾Hide ▴
Still missing
  • No de novo data available.
PP1 No co-segregation data available for this variant in affected families. Details ▾Hide ▴
Still missing
  • No family segregation data.
PP2 Insufficient data to assess whether MBD4 has a low rate of benign missense variation. No gene-level missense constraint metrics (Z-score, gnomAD missense o/e) are available in the evidence packet. HCI prior is not available for MBD4. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported.
  • No missense constraint metrics available.
Still missing
  • No gene-level missense constraint data (Z-score
  • o/e
  • missense depletion).
PP4 No patient phenotype or family history data specific to this case are available for review. Details ▾Hide ▴
Still missing
  • No phenotype data provided for this case.
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no classification exists.
Still missing
  • No external classification available.
Sources
clinvar ↗
BS2 No data available regarding observation of this variant in healthy adults for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No healthy adult observation data.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this variant. Details ▾Hide ▴
Still missing
  • No functional assay data for p.Pro30Leu.
BS4 No non-segregation data available for this variant in affected families. Details ▾Hide ▴
Still missing
  • No segregation or non-segregation data.
BP1 Although truncating MBD4 variants have been reported as pathogenic (e.g., c.217C>T/p.Gln73* in PMID:31322271), there is insufficient evidence that missense variants in MBD4 are not a disease mechanism. The gene-level evidence suggests a multi-tumor predisposition syndrome with LoF as a mechanism, but missense variants have not been systematically excluded. Details ▾Hide ▴
Evidence considered
  • MBD4 truncating variants reported as pathogenic (PMID:31322271
  • PMID:35460607).
  • Insufficient evidence to conclude missense variants are not pathogenic.
Still missing
  • No evidence that missense variants are excluded as a disease mechanism for MBD4.
BP2 No data on observation of this variant in trans with a pathogenic variant (recessive disorders) or in cis with a pathogenic variant (any inheritance). Details ▾Hide ▴
Still missing
  • No trans/cis observation data.
BP5 No data on an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data.
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no benign classification exists.
Still missing
  • No external benign classification available.
Sources
clinvar ↗
PS5 No alternative reputable source (ClinVar, VCEP, or clinical laboratory) has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar: variant absent
  • no classification exists.
Still missing
  • No external pathogenic classification available.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_003925.3:c.89C>T is a missense variant (p.Pro30Leu), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The PVS1 variant assessment confirms no eligibility under the ClinGen SVI generic PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant class is missense substitution
  • does not fall into any PVS1 null-variant bucket.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders; MBD4-associated disease (multi-tumor predisposition) is not established as a recessive condition, and no recessive context exists for this variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_003925.3:c.89C>T is a missense variant (p.Pro30Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
MBD4
Transcript
NM_003925.3
Coding (HGVS c.)
NM_003925.3:c.89C>T
Protein (HGVS p.)
NP_003916.1:p.(Pro30Leu)
GRCh38
chr3:129439745 G>A
GRCh37
chr3:129158588 G>A

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…
gnomAD v4.1 1 / 1,593,284 alleles AF 6.28e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.3e-07 · 1 / 1,593,284 alleles · 0 hom
European (non-Finnish)1 / 1,170,126 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.27634e-07; MAF= 0.00006%, 1/1593284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54609e-07; MAF= 0.00009%, 1/1170126 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -394 bp
0.000
SpliceAI acceptor gainat +184 bp
0.000
SpliceAI donor lossat +22 bp
0.000
SpliceAI donor gainat +197 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.016
BayesDel
-0.660

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.016 (strongly benign-predicting), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice alteration). All three independent in silico tools concordantly predict a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.016 (benign-predicting
  • threshold >0.5 for damaging).
  • BayesDel: −0.65999 (benign-predicting
  • positive scores indicate pathogenicity).
  • SpliceAI: max delta = 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of computational evidence support a benign effect. REVEL score is 0.016 (well below the 0.5 threshold, predicting benign), BayesDel score is −0.65999 (negative, consistent with benign), and SpliceAI max delta is 0.00 (no predicted splice impact). All available in silico predictors agree on a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.016 (benign-predicting).
  • BayesDel: −0.65999 (benign-predicting).
  • SpliceAI: max delta = 0.00 (no splice impact predicted).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_003925.3:c.89C>T is a missense variant (p.Pro30Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.016. BayesDel score = -0.65999.

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 1 / 1,593,284 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

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= 6.27634e-07; MAF= 0.00006%, 1/1593284 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54609e-07; MAF= 0.00009%, 1/1170126 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.016. BayesDel score = -0.65999.

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.