NM_001276270.2:c.1395C>T

MBD4 · NP_001263199.1:p.(Gly465=) · NM_001276270.2

GRCh37: chr3:129152089 G>A · GRCh38: chr3:129433246 G>A

Gene: MBD4 Transcript: NM_001276270.2

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 strong benign BP4 supporting benign BP7 supporting benign

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Gly465=)

gnomAD AF

0.11033981798033038 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001276270.2:c.1395C>T (p.Gly465=) is a synonymous variant in MBD4 present at extremely high frequency in population databases.

In gnomAD v2.1, this variant is observed in 32,849 of 282,718 alleles (AF=11.619%) including 2,604 homozygotes, with the highest subpopulation frequency in South Asians (AF=24.819%, 1,009 homozygotes).

In gnomAD v4.1, this variant is observed in 178,028 of 1,613,452 alleles (AF=11.034%) including 11,984 homozygotes.

The allele frequency far exceeds the BA1 stand-alone benign threshold of >1% in any general population, establishing this variant as a common polymorphism.

SpliceAI predicts no splicing impact (max delta score 0.02), consistent with the synonymous nature of this substitution.

Five clinical laboratories in ClinVar have classified this variant as Benign (ClinVarID 1262431), though review status is single-submitter level without expert panel consensus.

No functional studies, segregation data, or de novo observations for this variant were identified in the reviewed literature.

The very high population frequency (11.6% overall, thousands of homozygotes) alone is sufficient to classify this variant as Benign under generic ACMG/AMP 2015 framework.

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	Synonymous variant (p.Gly465=) does not trigger PVS1 null-variant framework. Variant bucket classified as 'other' in PVS1 variant assessment; no nonsense, frameshift, or canonical splice consensus disruption.	pvs1_variant_assessment
PS1	Not met	Synonymous variant produces no amino acid change (p.Gly465=). PS1 requires the variant to result in the same amino acid change as a previously established pathogenic variant, which cannot be satisfied by a synonymous substitution.
PS2	Not met	No de novo data identified for this variant. No publications or ClinVar submissions report confirmed de novo observation.	clinvar
PS3	Not met	No functional data identified for this variant. No publications report experimental characterization of NM_001276270.2:c.1395C>T or a systematically characterized range that includes this position. This is a synonymous variant with no predicted functional consequence.	oncokb
PS4	Not met	Extremely high population frequency (gnomAD AF 11.6%, 2,604 homozygotes) precludes case-control enrichment. A variant this common cannot demonstrate statistically significant enrichment in affected individuals, regardless of any case observations.	gnomad_v2 gnomad_v4
PS5	Not met	No evidence for PS5 (alternate pathogenic variant at same position in ClinVar) identified. The variant is synonymous; no alternate missense variant at the same residue exists to satisfy this criterion.	clinvar pm5_candidates
PM1	Not met	Synonymous variant (p.Gly465=) produces no amino acid change and therefore does not alter or remove any protein domain. No critical functional domain is affected by this silent substitution. Cancerhotspots.org does not flag this position as a significant hotspot.	pvs1_gene_context
PM2	Not met	Variant is present at very high frequency in gnomAD v2.1 (AF=11.619%, 32,849/282,718 alleles, 2,604 homozygotes) and v4.1 (AF=11.034%, 178,028/1,613,452 alleles, 11,984 homozygotes). PM2 requires absence or very low frequency (<0.1%), which is far exceeded.	gnomad_v2 gnomad_v4
PM5	N/A	Synonymous variant (p.Gly465=) — no amino acid change, no residue to compare against alternate pathogenic missense variants. PM5 candidate assessment confirms: unable to parse missense residue context.	pm5_candidates
PM6	Not met	No confirmed de novo observation for this variant in any publication or ClinVar submission. Assumed de novo without confirmation of maternity/paternity does not satisfy PM6.	clinvar
PP1	Not met	No segregation data available for this variant. No family studies or co-segregation analyses identified in the literature or ClinVar submissions.	clinvar
PP2	Not met	PP2 applies to missense variants in genes with low rate of benign missense variation and where missense is a common pathogenic mechanism. This variant is synonymous, not missense, and MBD4 has a loss-of-function mechanism with supporting truncating variants per PVS1 gene context.	pvs1_gene_context
PP3	Not met	Multiple lines of in silico evidence predict no deleterious effect. SpliceAI predicts no splicing impact (max delta score 0.02). REVEL and BayesDel scores are not available. No evidence supports a damaging prediction for this synonymous variant.	spliceai
PP4	Not met	No patient phenotype data specific to this variant available. The variant is too common (AF 11.6%) to be specifically associated with any rare disease phenotype.	gnomad_v2
PP5	Not met	ClinVar classification is Benign (ClinVarID 1262431) with review status 'criteria provided, single submitter' (1-star). PP5 requires 3-star expert panel review status to apply at supporting strength per current framework. ClinVar submission audit shows 5 clinical laboratories classified as Benign, but no expert panel review.	clinvar
BA1	Met	This variant is present at extremely high frequency in gnomAD v2.1 (AF=11.619%, 32,849/282,718 alleles, 2,604 homozygotes) and gnomAD v4.1 (AF=11.034%, 178,028/1,613,452 alleles, 11,984 homozygotes). Highest subpopulation frequency in South Asian population (v2.1 AF=24.819%, v4.1 AF=24.583%, grpmax FAF=24.313%). Far exceeds the BA1 threshold of >1% allele frequency in any general population. This variant is a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Met	Variant is present at allele frequencies far exceeding the expected frequency for any MBD4-related autosomal dominant disorder. gnomAD v2.1 AF=11.619% overall, with subpopulation frequencies ranging from 3.9% (Finnish) to 24.8% (South Asian). In every subpopulation, the frequency exceeds the BS1 threshold of >0.3%. The variant is observed in 2,604 homozygous individuals in v2.1 alone, incompatible with a highly penetrant Mendelian disease.	gnomad_v2 gnomad_v4
BS2	Met	The variant is observed in homozygous state in 2,604 individuals in gnomAD v2.1 and 11,984 individuals in gnomAD v4.1. For a gene where germline loss-of-function variants are associated with a multi-tumor predisposition syndrome (per PVS1 gene context), observation of this many homozygotes in population databases is incompatible with a pathogenic role. The homozygous count far exceeds what would be expected for a disease-causing variant.	gnomad_v2 gnomad_v4 pvs1_gene_context
BS3	Not met	No experimental functional studies demonstrating no deleterious effect were identified in the literature or OncoKB. While the synonymous nature and absence of splicing impact (SpliceAI max delta 0.02) are consistent with a benign effect, BS3 requires direct experimental evidence such as enzymatic assays or model organism studies showing no functional impact.	spliceai
BS4	Not met	No segregation data demonstrating lack of segregation with disease is available. No family studies involving this variant were identified.
BP1	N/A	BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous (p.Gly465=), not missense. The criterion does not apply.	pvs1_gene_context
BP2	Not met	No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder. While the variant is observed in homozygous state (2,604 homozygotes in gnomAD v2.1), the presence of homozygotes in a dominant disorder gene is better captured by BS2 and BA1 rather than BP2 (which requires specific trans configuration evidence).
BP4	Met	Multiple lines of computational evidence support no impact on splicing or gene product. SpliceAI predicts no splicing alteration (max delta score 0.02, below the 0.1 threshold). The variant is synonymous (p.Gly465=) and produces no amino acid change. No in silico tool predicts a damaging consequence.	spliceai
BP5	Not met	No evidence of an alternative molecular basis for disease in a patient carrying this variant. No case-level data with alternative molecular diagnoses is available.
BP6	Not met	ClinVar classification is Benign with review status 'criteria provided, single submitter' (1-star). BP6 requires 3-star expert panel review status to apply at supporting benign strength. Although 5 clinical laboratories submitted Benign classifications, the absence of expert panel consensus precludes BP6 application.	clinvar
BP7	Met	This is a synonymous variant (p.Gly465=) for which splice prediction algorithms predict no impact to the splice consensus sequence or creation of a new splice site (SpliceAI max delta score 0.02). The nucleotide at this position is not highly conserved, as evidenced by the extremely high population frequency (gnomAD AF 11.6%, 2,604 homozygotes), which is incompatible with a position under strong purifying selection.	spliceai gnomad_v2 gnomad_v4

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