Variant classification summary

NM_000321.3:c.1390-17T>A

RB1 · NP_000312.2:p.? · NM_000321.3

GRCh37: chr13:48954172 T>A · GRCh38: chr13:48380036 T>A

Gene: RB1 Transcript: NM_000321.3

Final call

VUS

BP4 supporting

Variant details

Gene

RB1

Transcript

NM_000321.3

Protein

NP_000312.2:p.?

gnomAD AF

0.00010725329784319099 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): SpliceAI max delta 0.024, below the 0.1 threshold - the intronic variant is not predicted to disrupt splicing.

2

Overall: VUS - under generic ACMG/AMP 2015 rules, a single supporting benign criterion does not reach Likely Benign.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion alone does not meet any benign, likely benign, likely pathogenic, or pathogenic combination threshold; therefore the classification is 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: this intronic variant lies 17 bases upstream of the exon boundary with no predicted null consequence (SpliceAI max delta 0.024).	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: PS1 requires a missense change at the protein level, and this intronic variant has no amino-acid consequence (p.?).
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or validated de novo status was available to evaluate PS2.
PS3	Not assessed	Not assessed: no variant-specific functional assay was available; the SpliceAI result is computational prediction only.
PS4	Not assessed	Not assessed: no case-control or cohort-enrichment evidence for this exact variant was available.	PMID:25356965 PMID:35802134
PM1	N/A	Not applicable: PM1 evaluates missense variants in critical domains, and this intronic variant has no protein residue.
PM2	Not met	Not met: the variant is present in gnomAD v2.1, v4.1, and gnomAD-Canada, so it is not absent from population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is a recessive-disorder criterion, and RB1 retinoblastoma is autosomal dominant.	PMID:35802134
PM4	Not met	Not met: this intronic single-nucleotide variant produces no protein-length change (p.?), unlike the in-frame indels PM4 targets.	pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: PM5 requires a pathogenic missense at the same amino-acid residue, and this intronic variant has none.
PM6	Not assessed	Not assessed: no case report or family study established the variant as apparently de novo.
PP1	Not assessed	Not assessed: no affected or unaffected relatives with informative segregation were documented.
PP2	N/A	Not applicable: PP2 is a missense criterion, and this intronic variant produces no missense substitution.
PP3	Not met	Not met: SpliceAI max delta 0.024 falls below the 0.2 PP3 threshold.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype indicating high specificity for RB1-related disease was available.
PP5	Not met	Not met: ClinVar holds only non-expert single-submitter Uncertain and Likely benign assertions, with no expert-panel submission.	clinvar
BA1	Not met	Not met: maximum observed allele frequency is 0.04358% (gnomAD-Canada), far below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not assessed	Not assessed: no RB1-specific or disease-derived maximum credible allele frequency was available to test against the observed 0.04358%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no homozygotes are reported, and population records do not confirm carriers are healthy adults.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating preserved RB1 function was available.
BS4	Not assessed	Not assessed: no confirmed non-carrier relatives were documented for non-segregation evaluation.
BP1	N/A	Not applicable: BP1 is a missense criterion, and this intronic variant has no amino-acid substitution to evaluate.
BP2	Not assessed	Not assessed: no second RB1 pathogenic variant or phase information was available for the trans/cis evaluation.	PMID:35802134
BP3	Not met	Not met: the variant is an intronic SNV, not an in-frame indel in a repetitive region.	pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI max delta 0.024 is below the 0.1 BP4 threshold, predicting no splice disruption.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no affected individual with this variant plus a separate explanatory molecular diagnosis was documented.
BP6	Not met	Not met: ClinVar shows no expert-panel submission; the non-expert Likely benign assertion alone cannot trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 covers synonymous coding variants; this intronic variant's splicing evidence was already applied as BP4.	spliceai 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.