NM_001276270.2:c.1382A>G

MBD4 · NP_001263199.1:p.(Asn461Ser) · NM_001276270.2

GRCh37: chr3:129152704 T>C · GRCh38: chr3:129433861 T>C

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

BP4 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(Asn461Ser)

gnomAD AF

0.00202099805830536 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

MBD4 NM_001276270.2:c.1382A>G (p.Asn461Ser) is a missense variant in exon 5 encoding a non-conservative amino acid substitution from asparagine to serine at codon 461.

This variant is present in gnomAD v4.1 at an allele frequency of 0.202% (3,262/1,614,054 alleles, including 8 homozygotes) and in gnomAD v2.1 at 0.169% (479/282,746 alleles, including 2 homozygotes), indicating it is not a rare variant in the general population.

Multiple lines of in silico evidence suggest no significant impact on the gene product: BayesDel scores -0.063 (benign) and SpliceAI predicts no splicing impact (max delta score 0.15). REVEL scores 0.54 (borderline deleterious) but does not overcome the preponderance of benign computational evidence (BP4 supporting).

No variant-specific functional studies, segregation data, de novo observations, or case-control studies were identified in the literature or ClinVar submissions.

ClinVar classifies this variant as Likely benign based on submissions from multiple clinical laboratories (4 Likely benign, 2 Uncertain significance), though the aggregate review status remains single-submitter level.

Overall, the only criterion met is BP4 at supporting strength. No pathogenic criteria are met. Insufficient evidence exists to classify this variant as either pathogenic or likely pathogenic; the classification is Uncertain Significance (VUS). The population frequency data and clinical laboratory consensus lean toward a benign interpretation but do not meet formal benign classification thresholds.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense variant (c.1382A>G, p.Asn461Ser), not a nonsense, frameshift, or canonical ±1,2 splice-site variant eligible for PVS1 under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at c.1382 has been reported as pathogenic. No evidence that a different amino acid substitution at this position is established as disease-causing.	clinvar
PS2	Not met	No de novo data are available for this variant. No confirmed de novo observation has been reported in ClinVar submissions or the literature.	clinvar
PS3	Not met	No variant-specific functional studies were identified. OncoKB reports Unknown Oncogenic Effect. A ClinVar submission (SCV002070998) explicitly notes the absence of functional studies for this variant. A separate submission (SCV004031892) references the variant's presence in uveal melanoma patients but provides no functional assay data.	oncokb clinvar
PS4	Not met	No case-control or statistical evidence demonstrates enrichment of this variant in affected individuals. No prevalence data comparing affected vs. unaffected populations are available.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No evidence that this is a well-established pathogenic variant identified in multiple unrelated affected individuals with the same phenotype. No variant-specific case reports with validated clinical data were identified.	clinvar
PM1	Not met	The variant (p.Asn461Ser) is not located in a statistically significant mutational hotspot (cancerhotspots.org analysis negative) and no well-characterized critical functional domain specific to this residue position was identified. While one ClinVar submission notes the variant is 'located in a domain of the MBD4 protein that is known to be functional,' this is a general domain-level statement without residue-specific functional characterization sufficient for PM1.	clinvar
PM2	Not met	This variant is present in gnomAD v2.1 at AF = 0.169% (479/282,746 alleles, 2 homozygotes) and in gnomAD v4.1 at AF = 0.202% (3,262/1,614,054 alleles, 8 homozygotes). Both exceed the 0.1% PM2 threshold for a rare variant absent from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue (p.Asn461) pathogenic comparator variant was identified in ClinVar. The pm5_candidates analysis found zero eligible comparator variants.	pm5_candidates
PM6	N/A	No de novo observation has been reported for this variant. PM6 requires confirmed de novo status with maternity and paternity confirmed.	clinvar
PP1	Not met	No segregation data are available for this variant. No family studies demonstrating cosegregation with disease have been reported.	clinvar
PP2	Not met	No gene-level constraint metrics (e.g., missense Z-score, missense o/e ratio) were available for MBD4 to establish a low rate of benign missense variation. Without quantitative constraint data, PP2 cannot be applied.
PP3	Not met	In silico predictors are conflicting. REVEL scores 0.54 (deleterious, >0.5 threshold), but BayesDel scores -0.063 (benign, <0 threshold) and SpliceAI predicts no splicing impact (max delta = 0.15). Only one of three computational tools supports a deleterious effect; multiple lines of concordant evidence are required for PP3.	revel bayesdel spliceai
PP4	N/A	No patient phenotype or clinical data are available for this variant. PP4 requires the variant to be identified in a patient with a phenotype highly specific for the gene/disease.
PP5	Not met	ClinVar classifies this variant as Likely benign (not Pathogenic) with a review status of 'criteria provided, single submitter' (1-star). PP5 requires a reputable source reporting the variant as pathogenic; a Likely benign classification does not support PP5. Additionally, per memory guidance, PP5 at supporting strength only applies when ClinVar review status is 3-star expert panel, which is not met here.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.202% (v2.1: 0.169%), well below the 1% BA1 threshold for a benign common variant.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v2.1 AF = 0.169% (grpmax FAF = 0.254%) and v4.1 AF = 0.202% (grpmax FAF = 0.236%). Both overall and population-maximum frequencies are below the 0.3% BS1 threshold for a dominant disorder.	gnomad_v2 gnomad_v4
BS2	Not met	While gnomAD reports homozygotes for this variant (2 in v2.1, 8 in v4.1), there is no confirmation that these individuals are healthy adults, which is required for BS2. Additionally, MBD4-associated tumor predisposition has variable age of onset and penetrance, making BS2 application from population databases alone inappropriate.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate that this variant has no deleterious effect. No in vitro or in vivo experimental data exist for p.Asn461Ser.	oncokb clinvar
BS4	Not met	No segregation data are available demonstrating lack of cosegregation with disease. No family studies have been reported for this variant.
BP1	Not met	MBD4 is not a gene for which primarily truncating variants are known to cause disease. The PVS1 gene-level analysis identified both truncating (c.217C>T/p.Gln73*) and missense variants in the disease literature. Additionally, this is a missense variant; BP1 specifically applies to missense variants in genes where the primary disease mechanism is through truncation.	pvs1_gene_context
BP2	Not met	No data are available demonstrating that this variant has been observed in trans with a pathogenic variant in MBD4 (for a recessive disorder) or in cis with a known pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel scores -0.063 (benign) and SpliceAI predicts no splicing impact (max delta = 0.15). While REVEL scores 0.54 (borderline deleterious), the preponderance of in silico tools (2 of 3) supports a benign interpretation.	bayesdel spliceai revel
BP5	Not met	No case has been reported in which this variant was observed together with an alternate molecular basis for disease in the same individual. No evidence of an explanatory second variant in MBD4 or another gene was identified.
BP6	Not met	ClinVar review status for Variation ID 1336001 is 'criteria provided, single submitter' (1-star), not 3-star expert panel. Per governing rules, BP6 at supporting strength requires ClinVar 3-star expert panel review. The variant's ClinVar classification (Likely benign) cannot be leveraged for BP6 at this review level.	clinvar
BP7	N/A	This is a missense variant (c.1382A>G, p.Asn461Ser), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants with no predicted splice impact.

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