Variant classification summary

NM_001276270.2:c.817G>A

MBD4 · NP_001263199.1:p.(Ala273Thr) · NM_001276270.2

GRCh37: chr3:129155670 C>T · GRCh38: chr3:129436827 C>T

Gene: MBD4 Transcript: NM_001276270.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Ala273Thr)

gnomAD AF

0.0840732089640089 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001276270.2:c.817G>A (p.Ala273Thr) in MBD4 is a common polymorphism present at 7.89–8.41% allele frequency across gnomAD datasets with 999–6,177 homozygous individuals, far exceeding the BA1 stand-alone benign threshold of >1%.

2

The variant is classified as Benign in ClinVar (Variation ID 1236752) with 2-star review status and five clinical laboratory submissions unanimously agreeing on a benign classification, consistent with the population frequency data.

3

Multiple in silico predictors support a benign effect: REVEL score 0.212 and BayesDel score -0.418, with no evidence of splicing impact from SpliceAI.

4

No pathogenic evidence was identified: PVS1 is not applicable to this missense variant; no functional studies (PS3), de novo events (PS2/PM6), segregation data (PP1), or case-control enrichment (PS4) were found.

5

Based on BA1 alone, this variant meets stand-alone benign criteria. Additional benign evidence from BS1, BS2, and BP4 further supports a benign classification. Classification: BENIGN.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_001276270.2:c.817G>A is a missense variant (p.Ala273Thr) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_variant_assessment
PS1	N/A	No same-residue comparator variant with a pathogenic classification was identified; the variant is a novel amino acid change (Ala273Thr) with no known pathogenic variant at this position.
PS2	Not met	No de novo data available for NM_001276270.2:c.817G>A. No literature or database reports of a confirmed de novo occurrence were identified.
PS3	Not met	No well-established functional studies directly testing NM_001276270.2:c.817G>A (p.Ala273Thr) or a systematically characterized range including this residue were identified. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional PMIDs. The domain-level mechanism data for MBD4 loss of function applies to truncating variants, not this missense substitution.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of NM_001276270.2:c.817G>A in affected individuals compared to population controls. The variant is highly prevalent in the general population (AF 7.89%), making any case-control enrichment unlikely.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and no equivalent PS5 rule is defined in the generic_acmg framework.
PM1	Not met	Residue 273 is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). No domain-level evidence was identified demonstrating that missense substitutions in the region of residue 273 disrupt a critical functional domain in a manner established for disease causation.
PM2	Not met	This variant is common in population databases. gnomAD v2.1: AF=7.89% (22,303/282,770 alleles, 999 homozygotes); gnomAD v4.1: AF=8.41% (135,695/1,614,010 alleles, 6,177 homozygotes). Far exceeds the PM2 threshold of <0.1% absent/rare.	gnomad_v2 gnomad_v4
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; no comparator pathogenic missense variants at the same codon (Ala273) were identified in ClinVar. The PM5 candidate harvesting returned no eligible comparators.	pm5_candidates
PM6	Not met	No confirmed de novo occurrence of NM_001276270.2:c.817G>A has been reported. No literature or database entries document a de novo event with confirmed maternity and paternity.
PP1	Not met	No cosegregation data are available for NM_001276270.2:c.817G>A. No family studies demonstrating segregation with disease have been reported.
PP2	Not met	MBD4 is not established as a gene with a low rate of benign missense variation and a high rate of pathogenic missense variants. Additionally, the high population frequency of p.Ala273Thr (AF 7.89%) suggests this is a common benign missense variant.	gnomad_v2 gnomad_v4
PP3	Not met	Multiple in silico predictors indicate a benign effect. REVEL score is 0.212 (below the 0.5 pathogenicity threshold) and BayesDel score is -0.418 (negative, predicting benign). No SpliceAI prediction is available, but there is no evidence of splicing impact.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype data are available for this case. There is no evidence that the patient's phenotype is highly specific for MBD4-related disease.
PP5	Not met	ClinVar classification for Variation ID 1236752 is Benign (not Pathogenic) with review status 'criteria provided, multiple submitters, no conflicts' (2-star). All six submitters classify as Benign. PP5 requires a reputable source reporting the variant as pathogenic; ClinVar consensus is Benign.	clinvar
BA1	Met	This variant is present at extremely high allele frequency in population databases, far exceeding the BA1 threshold of >1%. gnomAD v2.1: AF=7.89% (22,303/282,770 alleles, 999 homozygotes). gnomAD v4.1: AF=8.41% (135,695/1,614,010 alleles, 6,177 homozygotes). Highest subpopulation frequency in Ashkenazi Jewish: 16.24% (v2.1) / 16.28% (v4.1). The presence of 999–6,177 homozygotes across gnomAD datasets definitively establishes this as a common benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Met	Allele frequency far exceeds the BS1 threshold of >0.3%. gnomAD v2.1 AF=7.89% and gnomAD v4.1 AF=8.41% both vastly surpass the 0.3% cutoff. While BA1 (stand-alone benign) supersedes this criterion, the population data independently satisfies BS1 at strong benign strength.	gnomad_v2 gnomad_v4
BS2	Met	Observed in 999 homozygous individuals in gnomAD v2.1 and 6,177 homozygous individuals in gnomAD v4.1, definitively confirming observation in healthy adults. For MBD4-associated cancer predisposition syndromes (colorectal oligopolyposis, melanoma), this number of homozygotes is incompatible with a highly penetrant pathogenic role.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed on NM_001276270.2:c.817G>A (p.Ala273Thr) demonstrating no damaging effect on protein function or splicing. In silico predictions alone (REVEL, BayesDel) support BP4, not BS3.
BS4	Not met	No segregation data or family studies are available to assess whether this variant fails to segregate with disease in affected families.
BP1	Not met	MBD4 is not established as a gene in which only truncating variants cause disease. While loss-of-function variants are reported in association with MBD4-related tumor predisposition (PMID:31322271, PMID:35460607), it has not been demonstrated that missense variants at this gene cannot be pathogenic. BP1 cannot be applied.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic MBD4 variant. No data from recessive disease contexts are available.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.212 (well below the 0.5 pathogenicity threshold), and BayesDel score is -0.418 (negative, predicting benign). SpliceAI identifies no splicing impact. No HCI prior probability score is available for MBD4.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternative molecular basis for disease. No patient-level data are available for evaluation.
BP6	Not met	ClinVar Variation ID 1236752 is classified as Benign with review status 'criteria provided, multiple submitters, no conflicts' (2-star). The PP5/BP6 rule requires ClinVar 3-star expert panel status to automatically apply at supporting strength. Five clinical laboratories independently classify as Benign (GeneDx, Ambry Genetics, ARUP Laboratories, Labcorp/Invitae, Myriad Genetics), which is consistent with the BA1/BS1/BS2/BP4 evidence but does not independently meet the 3-star threshold for BP6 application under the current framework.	clinvar
BP7	N/A	NM_001276270.2:c.817G>A is a missense variant (p.Ala273Thr), not a synonymous/silent variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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