Variant classification summary

NM_001276270.2:c.335+27T>C

MBD4 · NP_001263199.1:p.? · NM_001276270.2

GRCh37: chr3:129156536 A>G · GRCh38: chr3:129437693 A>G

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.?

gnomAD AF

0.11031680271963852 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001276270.2:c.335+27T>C is a common intronic variant with an allele frequency of 11.6% in gnomAD v2.1 (32,839/282,596 alleles, 2,605 homozygotes) and 11.0% in gnomAD v4.1 (165,627/1,501,376 alleles, 11,308 homozygotes), far exceeding the 1% threshold for stand-alone benign (BA1).

2

The variant has been reported as Benign in ClinVar (ClinVar ID 1249121) by a clinical laboratory using criteria-based assessment.

3

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a deep intronic variant that does not disrupt normal mRNA processing (BP4, BP7).

4

The variant has been observed in homozygous state in 2,605 individuals in gnomAD v2.1 and 11,308 in gnomAD v4.1, demonstrating that homozygosity is tolerated at population scale (BS2).

5

Based on BA1 alone, this variant meets stand-alone benign criteria and is classified as Benign per the ACMG/AMP 2015 combining rules regardless of any other criterion.

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	This intronic variant (c.335+27T>C) is not a canonical null variant (nonsense, frameshift, or ±1,2 splice consensus); PVS1 is not applicable per ClinGen SVI PVS1 guidelines (PMC6185798).	pvs1_variant_assessment
PS1	N/A	This is an intronic variant with no amino acid change; PS1 (same amino acid change via different nucleotide substitution) does not apply.
PS2	Not met	No de novo observation data available for this variant.
PS3	Not met	No variant-specific functional data available. This is a common intronic polymorphism (AF 11.6%) with SpliceAI delta score of 0.00, providing no indication of functional consequence.
PS4	Not met	This variant is present at 11.6% allele frequency in gnomAD v2.1 with 2,605 homozygotes; case enrichment cannot be established for a variant of this frequency in the general population.	gnomad_v2 gnomad_v4
PS5	N/A	This is an intronic variant with no amino acid change; PS5 (different nucleotide change at same position producing same amino acid change as a known pathogenic variant) does not apply.
PM1	N/A	This is an intronic variant (c.335+27T>C) located outside coding sequence; PM1 (location in a critical functional domain) applies only to protein-coding regions or residues.
PM2	Not met	This variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles), far exceeding the <0.1% threshold for PM2. It is a common polymorphism, not absent from population databases.	gnomad_v2 gnomad_v4
PM5	N/A	This is an intronic variant with no amino acid change; PM5 (novel missense at a residue where a different pathogenic missense exists) does not apply.	pm5_candidates
PM6	Not met	No de novo observation data available for this variant.
PP1	Not met	No cosegregation data available for this variant.
PP2	N/A	This is an intronic variant, not a missense change; PP2 (missense variant in a gene with low rate of benign missense variation) does not apply.
PP3	Not met	SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No in silico evidence supports a pathogenic effect.	spliceai
PP4	Not met	No patient phenotype data available to evaluate whether the variant explains a specific clinical presentation.
PP5	Not met	ClinVar reports this variant as Benign, not Pathogenic. PP5 requires a pathogenic classification from a reputable source with supporting evidence. Furthermore, ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel), which does not meet the threshold for PP5 application.	clinvar
BA1	Met	This variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles, 2,605 homozygotes) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles, 11,308 homozygotes). The grpmax filtering allele frequency is 24.3%. These frequencies far exceed the 1% BA1 threshold, establishing this variant as a common benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Met	This variant is present at 11.6% in gnomAD v2.1, far exceeding the 0.3% BS1 threshold. Allele frequency is more than 38-fold above the cutoff across multiple populations, including South Asian (24.8%), African/African American (21.8%), and Ashkenazi Jewish (16.7%).	gnomad_v2 gnomad_v4
BS2	Met	This variant has been observed in 2,605 homozygotes in gnomAD v2.1 and 11,308 homozygotes in gnomAD v4.1. Homozygosity for this variant is tolerated at population scale, inconsistent with a fully penetrant Mendelian disorder.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not met	No family segregation data available to assess non-segregation with disease.
BP1	N/A	This is an intronic variant; BP1 (missense variant in a gene where truncating variants are the primary disease mechanism) does not apply.
BP2	Not met	No specific data on observation in trans with a pathogenic variant were identified in the case materials. Although the high population frequency (11.6%) makes co-occurrence statistically inevitable, direct evidence was not located.
BP4	Met	SpliceAI predicts no splicing impact (max delta score = 0.00) for this intronic variant. No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. Computational evidence supports a benign interpretation.	spliceai
BP5	Not met	No data available indicating an alternate molecular basis for disease in individuals carrying this variant.
BP6	Not met	ClinVar reports this variant as Benign (ClinVar ID 1249121), but the review status is 'criteria provided, single submitter' — not a 3-star expert panel classification. Per adjudication rules, BP6 is applied only with ClinVar 3-star expert panel support, which is not met here.	clinvar
BP7	Met	This is an intronic variant (c.335+27T>C) at a position not within the canonical splice consensus. SpliceAI predicts no splicing impact (max delta = 0.00). No evidence suggests this variant disrupts splicing, consistent with BP7.	spliceai
BP3	N/A	Skipped: trivially not applicable (in-frame indel criterion).
PM3	N/A	Skipped: trivially not applicable (recessive trans criterion, not a recessive disorder context).
PM4	N/A	Skipped: trivially not applicable (protein length change criterion; this is an intronic substitution).

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