Variant classification summary

NM_000321.3:c.13A>C

RB1 · NP_000312.2:p.(Thr5Pro) · NM_000321.3

GRCh37: chr13:48878061 A>C · GRCh38: chr13:48303925 A>C

Gene: RB1 Transcript: NM_000321.3

Final call

VUS

BP4 supporting

Variant details

Gene

RB1

Transcript

NM_000321.3

Protein

NP_000312.2:p.(Thr5Pro)

gnomAD AF

3.940352414434245e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): missense with REVEL 0.127, below the 0.250 benign-prediction threshold.

2

Overall VUS: BP4 alone does not reach the two benign-supporting criteria required for Likely Benign under generic ACMG/AMP 2015 combination rules.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting benign criterion alone is insufficient for Likely Benign, so the variant is classified as 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	N/A	Not applicable: this missense substitution does not trigger a null-variant mechanism such as nonsense-mediated decay, truncation, or canonical splice disruption.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated pathogenic report of a different nucleotide change producing p.Thr5Pro was available.	clinvar
PS2	Not assessed	Not assessed: no proband-specific de novo observation or parental testing was documented.
PS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating a damaging effect was available.	clinvar oncokb
PS4	Not assessed	Not assessed: no affected-case series, case-control comparison, or enrichment data for this variant was available.
PM1	Not met	Not met: no statistically significant cancer hotspot or RB1 domain evidence establishes residue 5 as a critical functional region.
PM2	Not met	Not met: the variant is present in gnomAD v4.1 (59/1,497,328 alleles), so it is not absent from population databases.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no observation places this variant in trans with a pathogenic variant.
PM4	N/A	Not applicable: missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no validated pathogenic missense comparator at RB1 codon 5 was available.	pm5_candidates
PM6	Not assessed	Not assessed: no suspected de novo occurrence without confirmed parentage was documented.
PP1	Not assessed	Not assessed: no family genotypes, informative meioses, or cosegregation results were available.
PP2	Not assessed	Not assessed: no gene-level analysis showing that benign RB1 missense variation is uncommon and disease-causing variants are predominantly missense.
PP3	Not met	Not met: REVEL score 0.127 falls below the PP3 threshold and in the benign-supporting range.	generic_acmg_combination_rules revel
PP4	Not assessed	Not assessed: no proband phenotype or clinical information linking the variant to an RB1-related disorder was available.
PP5	Not met	Not met: ClinVar holds no expert-panel Pathogenic or Likely pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.00394% is far below the 5% stand-alone benign threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not assessed	Not assessed: no RB1-specific maximum credible allele frequency model was available; the observed frequency is rare.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no phenotype-confirmed healthy adult carriers or validated unaffected-heterozygote count was available.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no variant-specific functional assay demonstrating a normal effect was available.	clinvar oncokb
BS4	Not assessed	Not assessed: no unaffected-carrier relatives or non-segregation data were provided.
BP1	Not assessed	Not assessed: no gene-specific analysis demonstrating that RB1 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no co-occurring pathogenic variant or in-trans phase determination was documented.
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): missense with REVEL 0.127, below the 0.250 BP4 benign-prediction threshold.	generic_acmg_combination_rules revel spliceai bayesdel
BP5	Not assessed	Not assessed: no evidence that an alternate molecular cause explains a phenotype in a carrier.
BP6	Not met	Not met: ClinVar holds no expert-panel Benign or Likely benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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