Variant classification summary

NM_001276270.2:c.1543+14C>T

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

GRCh37: chr3:129151927 G>A · GRCh38: chr3:129433084 G>A

Gene: MBD4 Transcript: NM_001276270.2

Final call

Benign

BA1 stand-alone benign BS2 strong benign BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.?

gnomAD AF

0.1449505019243741 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001276270.2:c.1543+14C>T is an intronic variant in MBD4 with an allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles, 8,420 homozygotes), far exceeding the BA1 stand-alone benign threshold.

2

The variant is present in homozygous state in 8,420 individuals in gnomAD v2.1 and 26,307 in gnomAD v4.1, meeting BS2 at strong benign strength, inconsistent with a pathogenic role in MBD4-associated disease.

3

SpliceAI predicts no splicing impact (max delta score = 0.00) for this +14 intronic variant, consistent with BP4 and BP7 at supporting benign strength.

4

ClinVar reports this variant as Benign by 3 clinical laboratories (variation ID 1236364), meeting BP6 at supporting benign strength.

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	Intronic variant at position c.1543+14, outside canonical +/-1,2 splice consensus. Does not qualify as a null variant under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework
PS1	N/A	Intronic variant with no coding amino acid change. PS1 requires a different nucleotide change at the same position resulting in the same predicted protein consequence.
PS2	Not met	No de novo observation reported for this variant in the available case materials.
PS3	Not met	No functional data exists for this intronic variant. Neither the two ClinVar-cited publications (PMID:25741868, PMID:28492532) nor any other source provides variant-specific functional evidence.
PS4	Not met	Variant is extremely common in population databases (gnomAD AF ~19.5%), precluding a statistically increased prevalence in affected individuals for any rare disease.	gnomad_v2 gnomad_v4
PS5	Not met	Variant is classified as Benign (not Pathogenic) by all ClinVar submitters. PS5 requires a pathogenic assertion from a reputable source.	clinvar
PM1	N/A	Intronic variant that does not map to a protein functional domain. PM1 requires the variant to be located in a well-established functional domain or critical hotspot.
PM2	Not met	Variant is present at very high frequency in gnomAD (v2.1 AF=19.55%, v4.1 AF=14.50%), far exceeding the PM2 threshold of <0.1%. Does not meet the absence/low-frequency requirement.	gnomad_v2 gnomad_v4
PM5	N/A	Intronic variant with no protein residue context. PM5 requires a different pathogenic missense change at the same amino acid residue.
PM6	Not met	No de novo observation reported for this variant. PM6 requires a de novo observation with confirmed maternity and paternity.
PP1	Not met	No co-segregation data available. Given the variant's extreme population frequency (~19.5%), co-segregation with any rare Mendelian disease would not be expected.
PP2	N/A	Not a missense variant. PP2 applies only to missense variants in genes with a low rate of benign missense variation.
PP3	Not met	SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No in silico tool predicts a pathogenic effect.	spliceai
PP4	Not met	Variant is present in ~19.5% of the general population, which is incompatible with a variant causing a rare disease with high specificity. The phenotype specificity required for PP4 cannot be met.	gnomad_v2 gnomad_v4
PP5	Not met	ClinVar reports this variant as Benign, not Pathogenic. PP5 requires a pathogenic assertion from a reputable source. ClinVar review status is 1-star (criteria provided, single submitter), not 3-star expert panel.	clinvar
BA1	Met	Allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles) and 14.50% in gnomAD v4.1 (233,804/1,612,992 alleles) far exceeds the BA1 threshold of >1% for generic ACMG. Highest subpopulation frequency is 48.47% in East Asian (gnomAD v2.1). The variant is observed in 8,420 homozygous individuals in v2.1 and 26,307 in v4.1.	gnomad_v2 gnomad_v4
BS1	N/A	BA1 is met at stand-alone benign strength. BS1 (>0.3% threshold) is superseded by the higher BA1 finding.
BS2	Met	Observed in 8,420 homozygous individuals in gnomAD v2.1 and 26,307 in v4.1, with no reported severe disease phenotype. Homozygous observation in a gene where germline LoF is associated with an autosomal dominant/recessive cancer predisposition syndrome strongly supports a benign interpretation.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect for this variant are available. SpliceAI delta of 0.00 indicates no splicing impact but is addressed under BP4/BP7 rather than BS3.
BS4	Not met	No segregation data available. However, given the extreme population frequency, lack of segregation with disease can be inferred but no formal study exists in the case materials.
BP1	N/A	Not a missense variant. BP1 applies specifically to missense variants in genes where truncating variants are the primary disease mechanism.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant is reported in the case materials.
BP4	Met	SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant, but the absence of any predicted splicing alteration supports a benign interpretation.	spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in cases with this variant in the available materials.
BP6	Met	ClinVar reports this variant as Benign by 3 clinical laboratories (GeneDx, ARUP Laboratories, Labcorp Genetics). Although the review status is 1-star (criteria provided, single submitter), three independent clinical laboratories agree on a benign classification, which constitutes a reputable source under generic ACMG BP6.	clinvar
BP7	Met	This is an intronic variant at position +14 from the exon 6 donor site with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. BP7 applies to synonymous and intronic variants where splicing prediction algorithms predict no impact on the splice consensus sequence.	spliceai

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