MBD4c.1177T>GLikely benign

Print report

Variant interpretation report

MBD4 c.1177T>G, p.(Phe393Val)

NM_003925.3:c.1177T>G NP_003916.1:p.(Phe393Val) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MBD4

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 2 Uncertain significance
Pipeline record: 4 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): This variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (1/1,613,932 alleles; 0.000062%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada v1.0.
BP1 (supporting): MBD4-associated disease is primarily caused by loss-of-function (truncating) variants, as supported by published germline cases (e.g., c.217C>T/p.Gln73*). This missense variant occurs in a gene where the predominant pathogenic mechanism is truncation, satisfying BP1.
BP4 (supporting): Multiple lines of computational evidence predict no deleterious impact: REVEL score 0.174 (tolerated, below the 0.5 damaging threshold), BayesDel score −0.216 (predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). This satisfies BP4 (supporting benign) with multiple concordant benign predictions.

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: 2

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (1/1,613,932 alleles; 0.000062%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 2

BP1Supporting

BP1 · supporting

MBD4-associated disease is primarily caused by loss-of-function (truncating) variants, as supported by published germline cases (e.g., c.217C>T/p.Gln73*). This missense variant occurs in a gene where the predominant pathogenic mechanism is truncation, satisfying BP1.

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence predict no deleterious impact: REVEL score 0.174 (tolerated, below the 0.5 damaging threshold), BayesDel score −0.216 (predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). This satisfies BP4 (supporting benign) with multiple concordant benign predictions.

Recorded classification: Likely 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: PM2 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely 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

1 / 1,613,932 alleles

gnomAD v4.1: 1 / 1,613,932 alleles. Recorded AF 6.19605e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

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

2 reported laboratory submissions

2 Uncertain significance.

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.

26 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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.

Two clinically validated in silico prediction algorithms (BayesDel, REVEL) plus a splicing predictor (SpliceAI) all return results inconsistent with pathogenicity, further supporting BP4.

Met · 3

PM2 SupportingThis variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (1/1,613,932 alleles; 0.000062%), well below the 0.1% PM2 threshold. It is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes).
gnomAD v4.1: 1 allele in 1
613
932 (AF=6.20×10⁻⁷
0.00006%)
0 homozygotes.
Absent from gnomAD-Canada v1.0.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP1 SupportingMBD4-associated disease is primarily caused by loss-of-function (truncating) variants, as supported by published germline cases (e.g., c.217C>T/p.Gln73*). This missense variant occurs in a gene where the predominant pathogenic mechanism is truncation, satisfying BP1. Details ▾Hide ▴

Evidence considered

MBD4 LOF mechanism supported by literature (nonsense variant c.217C>T/p.Gln73* reported in colorectal oligopolyposis).
Multi-tumor predisposition syndrome linked to germline MBD4 deficiency via truncating variants.

Sources

pvs1_gene_context

BP4 SupportingMultiple lines of computational evidence predict no deleterious impact: REVEL score 0.174 (tolerated, below the 0.5 damaging threshold), BayesDel score −0.216 (predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). This satisfies BP4 (supporting benign) with multiple concordant benign predictions. Details ▾Hide ▴

Evidence considered

REVEL: 0.174 (tolerated).
BayesDel: −0.216 (benign).
SpliceAI: max delta 0.00.

Sources

revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS2 No confirmed de novo occurrence data are available for this variant. Details ▾Hide ▴

Still missing

No de novo testing data in any published study.

PS3 No well-established in vitro or in vivo functional studies supportive of a damaging effect have been identified for this variant. Details ▾Hide ▴

Evidence considered

OncoKB reports Unknown Oncogenic Effect
no variant-specific functional studies found.

Still missing

No functional characterization of p.Phe393Val has been published.

Sources

oncokb ↗

PS4 The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls. Details ▾Hide ▴

Evidence considered

No case-control or cohort enrichment data available.

Still missing

No affected-vs-control allele frequency comparison has been performed.

PM1 This variant does not lie in a statistically significant mutational hotspot and is not located in a well-established critical functional domain where benign variation is absent. Details ▾Hide ▴

Evidence considered

Residue Phe393 is not in a statistically significant hotspot
no functional domain with constrained missense variation identified.

PM6 No confirmed de novo occurrence has been reported for this variant, with or without parental confirmation. Details ▾Hide ▴

Still missing

No de novo testing data available.

PP1 No segregation data are available for this variant in affected families. Details ▾Hide ▴

Still missing

No family-based segregation analysis has been reported.

PP2 MBD4-associated disease is primarily driven by loss-of-function (truncating) variants; there is insufficient evidence that missense variants are a common disease mechanism or that the gene has a low rate of benign missense variation, as required for PP2. Details ▾Hide ▴

Evidence considered

MBD4 disease mechanism is LOF via truncating variants
no missense constraint data (e.g.
Z-score) available.

Still missing

No gene-level missense constraint metric (e.g.
gnomAD missense Z-score) evaluated.

Sources

pvs1_gene_context

PP3 Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.174 (below the 0.5 damaging threshold), BayesDel score −0.216 (benign range), and SpliceAI max delta 0.00 (no predicted splicing impact). PP3 requires multiple lines of computational evidence supporting a deleterious effect, which is not met here. Details ▾Hide ▴

Evidence considered

REVEL: 0.174 (tolerated
<0.5).
BayesDel: −0.216 (predicted benign).
SpliceAI: max delta 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

PP4 No patient-specific phenotype or detailed clinical information is available to assess whether this variant segregates with a disease presentation specific for MBD4. Details ▾Hide ▴

Still missing

No detailed phenotype data for carriers of this variant.

PP5 No reputable source (expert panel or clinical laboratory with strong internal validation) has classified this variant as pathogenic. ClinVar records show only VUS classifications from two clinical laboratories. Details ▾Hide ▴

Evidence considered

ClinVar ID 3870863: two submitters
both assert Uncertain Significance
no expert panel review.

Sources

clinvar ↗

BA1 Allele frequency in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), well below the 1% BA1 stand-alone benign threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.000062% (1 allele)
far below 1% BA1 cutoff.

Sources

gnomad_v4 ↗

BS1 Allele frequency in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), well below the 0.3% BS1 threshold for a variant being too common to cause a highly penetrant disorder. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.000062%
far below 0.3% BS1 cutoff.

Sources

gnomad_v4 ↗

BS2 The single heterozygous observation in gnomAD v4.1 is insufficient to meet BS2 (observed in a healthy adult with full penetrance expected at an early age) without specific clinical confirmation that the individual was unaffected at an advanced age, especially given the variable penetrance of MBD4-associated cancer predisposition. Details ▾Hide ▴

Evidence considered

Single heterozygous allele in gnomAD v4.1
no clinical annotation for that individual
no homozygous observations.

Still missing

No clinical data on the single gnomAD v4.1 carrier.

Sources

gnomad_v4 ↗

BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant. Details ▾Hide ▴

Evidence considered

OncoKB reports Unknown Oncogenic Effect
no variant-specific functional evidence showing no impact.

Still missing

No functional characterization of p.Phe393Val has been published.

Sources

oncokb ↗

BS4 No evidence of non-segregation with disease has been reported for this variant in affected families. Details ▾Hide ▴

Still missing

No family-based non-segregation data available.

BP2 No evidence of this variant occurring in trans with a known pathogenic MBD4 variant has been reported; there is no observation in an autosomal recessive context. Details ▾Hide ▴

Still missing

No trans-phase data available.

BP5 No case has been identified in which this variant was found in a patient with an alternative molecular basis for disease that would explain the phenotype independently. Details ▾Hide ▴

Still missing

No co-occurrence data with alternative molecular diagnoses.

BP6 No reputable source has classified this variant as benign. ClinVar records show only Uncertain Significance classifications from two clinical laboratories. Details ▾Hide ▴

Evidence considered

ClinVar ID 3870863: two submitters classify as VUS
no expert benign classification exists.

Sources

clinvar ↗

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANM_003925.3:c.1177T>G (p.Phe393Val) is a missense variant; it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Variant is a missense substitution
PVS1 is restricted to null variants.

Sources

pvs1_generic_framework ↗pvs1_variant_assessment

PS1 N/ANo alternative pathogenic missense change at the same amino acid residue (Phe393) has been identified in ClinVar to support PS1 (same residue, different pathogenic change). Details ▾Hide ▴

Evidence considered

ClinVar contains only this variant at residue 393
classified as VUS.

Sources

clinvar ↗

PM5 N/ANo alternative pathogenic missense variant at the same amino acid residue (Phe393) was identified in ClinVar; PM5 requires a different pathogenic change at the same residue. Details ▾Hide ▴

Evidence considered

No same-residue comparator variants found
PM5 candidate harvesting returned zero candidates.

Sources

pm5_candidates

BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice consensus nor creation of a new splice site, and the nucleotide is not highly conserved. This is a missense variant, not a synonymous variant. Details ▾Hide ▴

Evidence considered

NM_003925.3:c.1177T>G is a missense variant (p.Phe393Val)
not a synonymous variant.

PS5 N/APS5 is not a criterion in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868); no CSPEC/VCEP framework defines a PS5 rule for MBD4. Details ▾Hide ▴

Evidence considered

PS5 is absent from the standard ACMG/AMP 2015 criteria.

Sources

generic_acmg_combination_rules

Identifiers

Gene: MBD4
Transcript: NM_003925.3
Coding (HGVS c.): NM_003925.3:c.1177T>G
Protein (HGVS p.): NP_003916.1:p.(Phe393Val)
GRCh38: chr3:129436467 A>C
GRCh37: chr3:129155310 A>C
ClinVar: 3870863

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

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in MBD4 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,613,932 alleles AF 6.2e-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 6.2e-07 · 1 / 1,613,932 alleles · 0 hom

European (non-Finnish)1 / 1,180,014

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= 6.19605e-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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.070

Other predictors

REVEL: 0.174
BayesDel: -0.216

How the predictions were used

Evidence considered

REVEL: 0.174 (tolerated).
BayesDel: −0.216 (benign).
SpliceAI: max delta 0.00.

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.174 (tolerated
<0.5).
BayesDel: −0.216 (predicted benign).
SpliceAI: max delta 0.00 (no splicing impact).

Sources

revelbayesdelspliceai ↗

Evidence considered

NM_003925.3:c.1177T>G is a missense variant (p.Phe393Val)
not a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.174. BayesDel score = -0.216133.

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

ACMG position statement on prenatal/preconception expanded carrier screening.

ACMG position statement providing recommendations for prenatal and preconception expanded carrier screening. MBD4 and NM_003925.3:c.1177T>G are not discussed in this paper.
Does not name this variant
PMID 23619275 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.

Cornel MC et al. · 2014

Expert opinion document outlining a framework for debating neonatal screening policies in the European Union. MBD4 and NM_003925.3:c.1177T>G are not discussed in this paper.
Does not name this variant
PMID 23652378 ↗
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. · 2015

Joint statement by ACMG, ACOG, NSGC, and SMFM on expanded carrier screening in reproductive medicine. MBD4 and NM_003925.3:c.1177T>G are not discussed in this paper.
Does not name this variant
PMID 25730230 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.

Botkin JR et al. · 2014

Guidelines from the Newborn Screening Translational Research Network (NBSTRN) on parental permission for pilot newborn screening research. MBD4 and NM_003925.3:c.1177T>G are not discussed in this paper.
Does not name this variant
PMID 24394680 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.

ACOG Committee Opinion providing guidance on newborn screening and the role of the obstetrician-gynecologist. MBD4 and NM_003925.3:c.1177T>G are not discussed in this paper.
Does not name this variant
PMID 31022120 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,932 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 2 Uncertain significance 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

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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.