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

Pathogenic

PVS1 very strong PP3 moderate PS3 supporting PM2 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

Pathogenic: PVS1 very strong is supported by RNA evidence of an 88-base splice deletion and premature p.Arg83Profs*5 truncation.

2

Pathogenic: PP3 moderate is supported by a SpliceAI maximum delta of 0.81.

3

Pathogenic: PS3 supporting is supported by exact-variant RNA-seq evidence of aberrant splicing and premature termination.

4

Pathogenic: PM2 supporting is supported by a gnomAD maximum allele frequency of 3.21875e-05 and zero homozygotes.

Final determination: Under the generic ACMG/AMP fallback, the adjudicated combination of PVS1 very strong with PP3 moderate, PS3 supporting, and PM2 supporting leads to a Pathogenic call.

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: RNA evidence shows c.335+1G>A causes an 88-base splice deletion and premature p.Arg83Profs*5 truncation.	pvs1_generic_framework pvs1_gene_context PMID:29760383 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: parental genotypes and confirmed maternity and paternity are not documented for the reported germline variant.	PMID:29760383 PMID:32239153
PS3	Met	Met at supporting: RNA-seq showed c.335+1G>A activated a cryptic donor, deleted 88 bases, and produced a premature stop codon.	PMID:29760383
PS4	Not assessed	Not assessed: the exact variant was observed in 2 of 1093 uveal melanoma patients, but no control frequency or enrichment statistic is available.	generic_acmg_combination_rules 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 overall AF is 2.36811e-05, below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: target-variant reports lack a documented second germline pathogenic MBD4 allele in trans or confirmed biallelic inheritance.	PMID:29760383 PMID:30049810 PMID:32239153
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: no documented apparently de novo observation exists, even though parental testing is unavailable.	PMID:29760383 PMID:32239153
PP1	Not assessed	Not assessed: two reported patients do not establish familial co-segregation without affected relatives, relationships, and informative meioses.	PMID:32239153
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	Met	Met: SpliceAI maximum delta 0.81 meets the >=0.5 PP3 moderate threshold.	spliceai
PP4	Not met	Not met: uveal melanoma and glioblastoma are reported with the variant, but neither phenotype is highly specific for a single-gene MBD4 diagnosis.	generic_acmg_combination_rules PMID:32239153 PMID:29760383
PP5	Not met	Not met: ClinVar lists the exact variant as Likely pathogenic, but the record has 0 expert-panel submissions and only single-submitter laboratory assertions.	clinvar
BA1	Not met	Not met: the highest observed allele frequency is 3.21875e-05, far below the generic BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the highest observed allele frequency is 3.21875e-05, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: gnomAD reports zero homozygotes for this variant across the available v2.1, v3.1 non-cancer, and v4.1 datasets.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no benign assay for c.335+1G>A was identified, while the exact-variant RNA result showed aberrant splicing and premature termination.
BS4	Not assessed	Not assessed: no informative affected relatives lacking the variant or documented family-level non-segregation analysis is available.	PMID:29760383 PMID:32239153
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: no reported cis or trans phase between c.335+1G>A and another pathogenic germline variant is available.	PMID:29760383 PMID:32239153
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	Not met	Not met: SpliceAI maximum delta 0.81 exceeds the <=0.1 BP4 supporting threshold.	spliceai
BP5	Not assessed	Not assessed: no alternative disease-causing variant or established molecular diagnosis explaining the phenotype is documented.	generic_acmg_combination_rules PMID:32239153 PMID:29760383
BP6	Not met	Not met: the exact ClinVar record is Likely pathogenic with 0 expert-panel submissions, not an expert-panel Benign or Likely benign classification.	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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