Variant classification summary

NM_006015.5:c.1217_1229dup

ARID1A · NP_006006.3:p.(Pro411ThrfsTer216) · NM_006015.5

GRCh37: chr1:27056216 A>ACAGGGACCTCCGT · GRCh38: chr1:26729725 A>ACAGGGACCTCCGT

Gene: ARID1A Transcript: NM_006015.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

ARID1A

Transcript

NM_006015.5

Protein

NP_006006.3:p.(Pro411ThrfsTer216)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): the 13-bp frameshift is predicted to trigger nonsense-mediated decay, and loss of function is an established ARID1A disease mechanism.

2

PM2 (Supporting): the exact 13-bp duplication is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

3

Overall: Likely Pathogenic under generic ACMG/AMP 2015 combination rules (PVS1 very strong + PM2 supporting).

Final determination: 1 PVS1 (very strong) + 1 supporting-strength criterion (PM2) → Likely Pathogenic per the ClinGen SVI 2020 PM2-downgrade addendum (Post_P 0.988).

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 (Very Strong): the 13-bp frameshift creates a premature stop at codon 626 predicted to trigger nonsense-mediated decay.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: this frameshift produces no altered amino acid to compare against an established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: parental genotypes confirming a de novo occurrence are unavailable.
PS3	Not assessed	Not assessed: no functional assay evidence specific to this variant was available.
PS4	Not assessed	Not assessed: no case-control or affected-cohort data for this exact variant were available.
PM1	N/A	Not applicable: hot-spot and critical-domain criteria apply to missense variants, not frameshifts.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): the exact 13-bp duplication is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no phase data, in-trans pathogenic variant, or affected-proband observations were available.
PM4	N/A	Not applicable: PM4 concerns protein length changes, and this frameshift does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: parental testing documenting a presumed de novo occurrence is unavailable.
PP1	Not assessed	Not assessed: no segregation data from affected relatives were available.
PP2	N/A	Not applicable: PP2 applies to missense variants, so missense-constraint assessment is irrelevant for this frameshift.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.108 falls in the gray zone (0.1-0.2), meeting neither PP3 nor BP4.	spliceai
PP4	Not assessed	Not assessed: no phenotype evidence indicating an ARID1A-specific presentation was available.
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, so no stand-alone benign frequency threshold is reached.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population databases, so no allele frequency above the disease-prevalence threshold is available.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy homozygous individuals or genotype-quality data were available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay showing no damaging effect for this variant was available.
BS4	Not assessed	Not assessed: no unaffected relatives or non-segregation analysis were available.
BP1	N/A	Not applicable: BP1 applies to missense variants, and this frameshift is the disease-causing variant class.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase-resolved allelic observations were available.
BP3	N/A	Not applicable: BP3 concerns in-frame changes in repetitive regions, which this frameshift is not.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.108 exceeds the BP4 threshold of <0.1 and falls in the indeterminate gray zone.	spliceai
BP5	Not assessed	Not assessed: no alternative molecular etiology or phenotype information was available.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this frameshift alters the protein sequence.	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.