Variant classification summary

NM_001276270.2:c.-1G>A

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

GRCh37: chr3:129158677 C>T · GRCh38: chr3:129439834 C>T

Gene: MBD4 Transcript: NM_001276270.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MBD4

Transcript

NM_001276270.2

Protein

NP_001263199.1:p.(=)

gnomAD AF

0.00022575244596245172 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 frequency 0.02258% falls below the 0.1% rare-variant threshold.

2

BP4 (Supporting): SpliceAI maximum delta 0.00 falls below the 0.10 threshold, indicating no predicted splice impact.

3

Synthesis: one supporting pathogenic criterion and one supporting benign criterion do not meet an ACMG/AMP 2015 combination threshold, so the classification remains VUS.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion plus one supporting benign criterion meets no pathogenic, likely pathogenic, benign, or likely benign combination, yielding 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	Not met	Not met: c.-1G>A is a 5'-UTR change with SpliceAI delta 0.00, not a nonsense, frameshift, or canonical splice variant.	pvs1_generic_framework pvs1_gene_context spliceai
PS1	N/A	Not applicable: the variant produces no amino acid change (p.(=)), so no same-residue pathogenic missense comparison exists.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes or de novo testing results were available for this variant.
PS3	Not assessed	Not assessed: no variant-specific functional assay results were available, and computational splice prediction cannot substitute.
PS4	Not assessed	Not assessed: no affected-case series or case-control enrichment data were provided for this variant.
PM1	N/A	Not applicable: p.(=) alters no residue, so hot-spot or critical-domain membership cannot be evaluated.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): gnomAD v4.1 frequency 0.02258% is below the 0.1% rare-variant threshold, though the variant is not absent.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no pathogenic allele in trans and no phase or inheritance data were available for this recessive-disease criterion.
PM4	N/A	Not applicable: the variant causes no protein length change, so the in-frame indel and stop-loss premises do not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change occurs at this residue, so no different pathogenic missense comparison exists.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental or clinical information establishing a likely de novo occurrence was available.
PP1	Not assessed	Not assessed: no informative relatives or segregation observations were available to evaluate co-segregation with disease.
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint profile cannot be evaluated.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta 0.00 does not exceed the >0.20 PP3 supporting threshold for predicted splice impact.	spliceai pvs1_variant_assessment
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specificity evidence was available for this exact variant.
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists; both exact-variant submissions are uncertain significance.	clinvar
BA1	Not met	Not met: gnomAD v4.1 frequency 0.02258% is far below the 1% BA1 threshold for stand-alone benign classification.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest population frequency, 0.02899%, is below the 0.3% BS1 threshold for elevated frequency.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: 363 gnomAD v4.1 alternate alleles include zero homozygotes, so no healthy-homozygote evidence supports BS2.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no controlled functional experiment demonstrating preserved normal protein function was available.
BS4	Not assessed	Not assessed: no tested unaffected relatives or phenotype-defined non-segregation observations were available.
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-variant disease mechanism is irrelevant here.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no documented in-trans or in-cis pathogenic allele and no phase information were available.
BP3	N/A	Not applicable: the variant does not alter protein length within a repeat region, so BP3 has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI maximum delta 0.00 is below the <0.10 BP4 threshold, supporting no predicted splice impact.	spliceai
BP5	Not assessed	Not assessed: no case was reported in which an alternative molecular diagnosis fully explained the phenotype.
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign classification exists; both exact-variant submissions are uncertain significance.	clinvar
BP7	N/A	Not applicable: this is not a synonymous variant, so the silent-variant premise for BP7 does not hold.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.