Classification rationale

BS1BP1BP4 Likely Benign

MBD4 c.1684G>C missense · exon 8

Likely Benign: BS1 (strong) - gnomAD v4.1 grpmax filtering AF 1.047% (South Asian 1.104%) exceeds the 1% threshold, with 71 homozygotes reported. Likely Benign: BP4 (moderate) - REVEL 0.178 falls in the benign band (at or below 0.183) for this missense change. Likely Benign: BP1 (supporting) - missense variant in MBD4, a gene in which disease is caused primarily by truncating loss-of-function variants. Likely Benign: combination - one strong benign (BS1) plus one supporting benign (BP1) criterion; no pathogenic criterion met and BA1 not met, so the call is Likely Benign rather than Benign.

BS1 + BP1 + BP4 → Likely Benign

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.

Gene diagram · NM_001276270.2 · variants mapped to exon structure

MBD4 NM_001276270.2

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BS1 strong review Benign

Met at strong: gnomAD v4.1 grpmax filtering AF of 1.047% exceeds the 1% BS1 threshold (South Asian AF 1.10%).

gnomAD v4.1 all-comers (gnomad_v4): total AF 0.71835% (11,588/1,613,132 alleles); grpmax filtering AF 1.04703%; South Asian ancestry AF 1.10376% (1,005/91,052 alleles, 18 homozygotes); Amish AF 3.07018% (28/912 alleles); 71 homozygotes overall.gnomAD v2.1 all-comers (gnomad_v2): total AF 0.51110% (1,444/282,528 alleles); grpmax filtering AF 0.87948%; South Asian ancestry AF 0.97021% (297/30,612 alleles, 7 homozygotes); 12 homozygotes overall.gnomAD-Canada v1.0 (gnomad_canada): total AF 0.66225% (122/18,422 alleles), 0 homozygotes; South Asian ancestry 18/1,362 alleles (1.32%, FAF95 0.854%).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:25741868 ↗

BP1 supporting Benign

Met at supporting strength: MBD4-associated disease is caused primarily by truncating loss-of-function variants, and no MBD4 missense variant has reached established pathogenic status.

BP1 definition used: 'Missense variant in a gene for which primarily truncating variants are known to cause disease' (ACMG/AMP 2015 criteria, PMID:25741868, Table 4; BP1 is a supporting-strength benign criterion with no stronger weighting available).Variant type confirmed as missense: NM_001276270.2:c.1684G>C -> NP_001263199.1:p.(Asp562His), consequence class 'missense' (prefetch/variant assessment), which is the variant class BP1 addresses.pvs1_gene_context (record key 'pvs1_gene_context'): lof_mechanism_supported = true; mechanism_rationale states that a targeted germline literature review identified publications supporting MBD4 loss of function as a germline disease mechanism; disease_names reference a germline MBD4 mutation (c.217C>T/p.Gln73*, a stop-gain) in a patient with colorectal oligopolyposis and early-onset cancer, i.e. truncated-protein disease.

clinvar ↗PMID:25741868 ↗

BP4 moderate Benign

Met at moderate strength: REVEL 0.178 is at or below the 0.183 moderate BP4 threshold for this missense variant.

Variant consequence settled as missense, p.(Asp562His) (NP_001263199.1), which places BP4 on the REVEL protein-impact path and makes BP4 applicable.Local REVEL v1.3 lookup returned revel_score = 0.178 for chr3:129431542 C>G (GRCh38), carried in the case as revel.revel_score.Thresholds applied verbatim from the supplied ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet, PMID:36413997): BP4 supporting <= 0.29, moderate <= 0.183, strong <= 0.016. 0.178 clears the moderate band and does not reach the strong band (<= 0.016).

Assessed · not applied · 13 not met · 8 not assessed

Pathogenic

PS1 Not met: no MBD4 variant with a different nucleotide change encodes p.(Asp562His), and this amino acid change has no established pathogenic classification in ClinVar.

PS2 Not assessed: no proband or parental-testing data exist, and the variant is common in gnomAD (v4.1 AF 0.72%, 71 homozygotes), so a confirmed de novo occurrence is unsupported.

PS3 Not assessed: no functional assay for MBD4 p.(Asp562His) was found in ClinVar, OncoKB, COSMIC or the literature, so the PS3 assay requirement is unmet.

PS4 Not met: no case-control enrichment study exists for c.1684G>C, and gnomAD v2.1 AF 0.005111 (1444 alleles, 12 homozygotes) is inconsistent with case enrichment.

PM1 Not met: CancerHotspots reports no significant hotspot at D562 and the codon carries benign variation, including 12 gnomAD v2.1 homozygotes at 0.51% allele frequency.

PM2 Not met: gnomAD v4.1 all-comers AF 0.718% (11,588 alleles) far exceeds the 0.0001 PM2 supporting threshold.

PM3 Not met: no pathogenic MBD4 variant in trans with c.1684G>C, and gnomAD v4.1 shows 71 homozygotes (AF 0.72%) at this allele.

PM5 Not met: no missense variant introducing a different amino acid at codon 562 is established pathogenic - the only other ClinVar codon-562 entry is a benign synonymous change.

PM6 Not assessed: no submission or publication reports this variant as de novo, and gnomAD v4.1 lists 71 homozygotes, arguing against a rare de novo allele.

PP1 Not assessed: no affected family members were genotyped, so co-segregation with disease cannot be evaluated for this variant.

PP2 Not met: MBD4-associated disease is attributable to loss-of-function variants rather than missense, and no gene-level missense-constraint metric is available to satisfy PP2.

PP3 Not met: REVEL 0.178 is below the 0.644 supporting threshold for PP3 in this missense variant.

PP4 Not assessed: no proband phenotype or HPO terms were provided, and the only available labels ('Inborn genetic diseases', 'not specified') carry no specificity.

PP5 Not met: ClinVar variation 218624 has zero expert-panel submissions, all seven being single-submitter clinical laboratories with conflicting classifications (1-star review status).

Benign

BA1 Not met: the highest credible population frequency is 3.07% (gnomAD v4.1 Amish), below the 5% BA1 stand-alone threshold.

BS2 Not met: 71 gnomAD v4.1 homozygotes exist, but BS2 requires a fully penetrant early-onset disorder and MBD4 predisposition is adult-onset.

BS3 Not assessed: no functional assay showing normal/benign MBD4 p.(Asp562His) function was found in any consulted source, so BS3's assay requirement is unmet.

BS4 Not assessed: no family genotypes are available, and the only ClinVar mention of non-segregation is a templated comment, not a segregation observation.

BP2 Not met: no cis/trans phase with a pathogenic MBD4 variant, and MBD4 predisposition is bi-allelic recessive (Palles et al.

BP5 Not assessed: no proband genotype or co-occurring variant information is available to determine whether an alternate molecular basis explains the phenotype.

BP6 Not met: the benign-leaning ClinVar majority comes from single-submitter clinical laboratories with zero expert-panel submissions, which BP6 does not accept.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00718354; MAF= 0.71835%, 11588/1613132 alleles, homozygotes = 71) and has highest observed frequency in the Amish population (AF= 0.0307018; MAF= 3.07018%, 28/912 alleles, homozygotes = 0); grpmax FAF= 0.0104703.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.005111; MAF= 0.51110%, 1444/282528 alleles, homozygotes = 12) and has highest observed frequency in the South Asian population (AF= 0.00970208; MAF= 0.97021%, 297/30612 alleles, homozygotes = 7); grpmax FAF= 0.00879484.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.006622516556291391, 122/18422 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.72% · 11588 / 1,613,132
71 hom · FAF 1%

Amish 28 / 912	3.1%
South Asian 1005 / 91,052	1.1% 18 hom
Ashkenazi Jewish 252 / 29,596	0.85% 4 hom
European (non-Finnish) 9424 / 1,179,718	0.8% 47 hom
Remaining individuals 488 / 62,470	0.78% 2 hom
Middle Eastern 41 / 5,994	0.68%
Admixed American 226 / 60,028	0.38%
African/African American 91 / 75,022	0.12%
European (Finnish) 31 / 63,490	0.049%
East Asian 2 / 44,850	0.0045%

gnomAD v2.1

0.51% · 1444 / 282,528
12 hom · FAF 0.88%

South Asian 297 / 30,612	0.97% 7 hom
Ashkenazi Jewish 87 / 10,368	0.84%
Remaining individuals 50 / 7,222	0.69%
European (non-Finnish) 851 / 129,128	0.66% 5 hom
Admixed American 124 / 35,434	0.35%
African/African American 23 / 24,958	0.092%
European (Finnish) 10 / 24,854	0.04%
East Asian 2 / 19,952	0.01%

gnomAD Canada 🇨🇦

0.66% · 122 / 18,422
0 hom · FAF 0.85%

Middle Eastern 2 / 144	1.4%
South Asian 18 / 1,362	1.3%
Ashkenazi Jewish 8 / 832	0.96%
European (non-Finnish) 82 / 11,742	0.7%
Latino/Admixed American 5 / 838	0.6%
Remaining individuals 6 / 1,138	0.53%
African/African American 1 / 1,020	0.098%

+ 2 not observed (East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 218624)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.178. BayesDel score = -0.306477.

SpliceAI ↗

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: not classified.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 2 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

23169492 ↗ The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.

23652378 ↗ A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.

24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency.

25626707 ↗ Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.

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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

31022120 ↗ ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist. CLINVAR

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