Variant classification summary

NM_001276270.2:c.335+1G>A

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

GRCh37: chr3:129156562 C>T · GRCh38: chr3:129437719 C>T

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

PVS1 very strong PS3 supporting PM2 supporting BP4 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.?

gnomAD AF

2.3681147064908776e-05 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): canonical +1 splice variant produces an early truncating consequence.

2

PS3 (supporting): exact-variant RNA-seq showed abnormal splicing and a premature stop codon.

3

PM2 (supporting): gnomAD v4.1 allele frequency is 2.36811e-05 with zero homozygotes.

4

BP4 (supporting): SpliceAI maximum delta 0.00 meets the benign splicing-prediction threshold.

Final determination: Under the generic ACMG/AMP fallback, PVS1 very strong plus PS3 and PM2 supporting would support Pathogenic, but the conflicting BP4 supporting benign evidence requires VUS.

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	Met	Met at very strong: canonical +1 splice variant c.335+1G>A is reported as p.Arg83Profs*5 with an early premature stop in the MANE transcript.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:29760383 PMID:30049810 PMID:32239153
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented parental genotypes or validated de novo observation is available for the exact c.335+1G>A variant.	PMID:32239153 PMID:29760383
PS3	Met	Met at supporting: tumor RNA-seq for c.335+1G>A showed cryptic donor use, 88-base loss, and a premature stop codon.	PMID:29760383
PS4	Not assessed	Not assessed: the exact variant occurred in 1 of 1,093 uveal melanoma patients, but no case-control comparison or enrichment statistic is available.	PMID:32239153 PMID:29760383
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 allele frequency 2.36811e-05 is below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no report establishes c.335+1G>A in trans with a second pathogenic MBD4 allele or documents biallelic disease for this specific variant.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: the exact variant is reported in germline cases, but no suspected de novo event without parental testing is documented.	PMID:32239153 PMID:29760383
PP1	Not assessed	Not assessed: two unrelated reports establish recurrence, but provide zero informative familial meioses demonstrating co-segregation.	PMID:32239153 PMID:29760383
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.00 is below the >=0.2 supporting PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: the exact variant appears in uveal melanoma and glioblastoma reports, but no sufficiently specific individual phenotype rule is documented.	PMID:32239153 PMID:29760383
PP5	Not met	Not met: ClinVar has an exact-variant Likely pathogenic label, but expert-panel submissions for this variant number 0.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 2.36811e-05, far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD v4.1 population frequency is 3.21875e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not provide sufficient healthy-adult phenotype or penetrance evidence for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay for c.335+1G>A demonstrated preserved MBD4 splicing or function.
BS4	Not assessed	Not assessed: no unaffected relatives with informative genotypes and phenotypes are reported to demonstrate non-segregation.	PMID:32239153 PMID:29760383
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: phase with another pathogenic MBD4 allele is unreported, so the cis/trans observation required for BP2 is unavailable.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: SpliceAI maximum delta 0.00 meets the <=0.1 supporting BP4 threshold.	spliceai
BP5	Not assessed	Not assessed: no alternative molecular etiology or BP5 likelihood-ratio value with a governing threshold is documented.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign assertion, and the available submissions are non-expert Likely pathogenic.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001276270.2:c.335+1G>A in MBD4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001263199.1:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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