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

PM2 supporting 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

PM2 (Supporting): variant is very rare in population databases (gnomAD v4.1 AF 0.01073%; no homozygotes).

2

BP4 (Supporting): SpliceAI max delta 0.024 is below the <0.1 threshold, predicting no significant splice impact.

3

Synthesis: PM2 and BP4 at supporting strength satisfy no ACMG/AMP 2015 pathogenic or benign combination rule, so the variant is classified as VUS.

Final determination: 1 supporting pathogenic (PM2) + 1 supporting benign (BP4) does not meet any combining rule, defaults to Uncertain Significance.

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	N/A	Not applicable: deep intronic variant (17 bp upstream of the exon 14 splice site) with no established null-variant mechanism.	pvs1_generic_framework
PS1	N/A	Not applicable: intronic variant with no amino-acid change (NP_000312.2:p.?) to compare against.
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with parental testing and parentage confirmation was documented.
PS3	Not assessed	Not assessed: no functional or splicing assay data for this variant was available.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this variant was retrieved.
PM1	N/A	Not applicable: no protein sequence change (p.?) exists to assess against a functional domain or hotspot.
PM2	Met	Met (supporting): very rare in population databases, gnomAD v4.1 AF 0.01073% with no homozygotes.	gnomad_canada gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no evidence establishes this variant in trans with a pathogenic RB1 variant.
PM4	N/A	Not applicable: intronic substitution with no in-frame deletion/insertion or stop-loss change in protein length.
PM5	N/A	Not applicable: intronic variant produces no amino-acid substitution, so no residue-level pathogenic comparator exists.
PM6	Not assessed	Not assessed: no presumed de novo occurrence of this variant in an affected individual was documented.
PP1	Not assessed	Not assessed: no segregation data on affected or unaffected relatives was available.
PP2	N/A	Not applicable: not a missense variant, so missense-based PP2 does not apply.
PP3	Not met	Not met: SpliceAI max delta 0.024 versus the >0.2 PP3 threshold.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype, age of onset, or family history data was supplied.
PP5	Not met	Not met: ClinVar has no expert-panel submission for this variant.	clinvar
BA1	Not met	Not met: highest population frequency 0.05987% versus the >1% BA1 threshold.	gnomad_canada gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS1	Not met	Not met: highest population frequency 0.05987% versus the >0.3% BS1 threshold.	gnomad_canada gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no homozygotes observed, but no healthy-adult cohort data demonstrating unaffected carriers either.	gnomad_canada gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal, no-effect function for this variant.
BS4	Not assessed	Not assessed: no unaffected-carrier or non-segregation observations were documented.
BP1	N/A	Not applicable: not a missense variant, so BP1 does not apply.
BP2	Not assessed	Not assessed: no phase or genotype data to establish trans or cis configuration with a pathogenic variant.
BP3	N/A	Not applicable: single-nucleotide intronic substitution, not an in-frame indel in a repeat region.
BP4	Met	Met (supporting): SpliceAI max delta 0.024, below the <0.1 BP4 threshold, predicting no splice impact.	spliceai
BP5	Not assessed	Not assessed: no carrier with an independently established alternate molecular diagnosis was found.
BP6	Not met	Not met: only non-expert ClinVar submissions exist, with no expert-panel assertion.	clinvar
BP7	N/A	Not applicable: deep intronic substitution, not a synonymous coding change.

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.