Variant classification summary

NM_000321.3:c.*1G>C

RB1 · NP_000312.2:p.? · NM_000321.3

GRCh37: chr13:49054208 G>C · GRCh38: chr13:48480072 G>C

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

6.212893493609418e-07 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant seen once in 1,609,556 gnomAD v4.1 alleles (AF 6.2e-07), far below the 0.1% rarity threshold.

2

BP4 (Supporting): SpliceAI max delta 0.007, well below the <0.1 threshold, indicating no predicted splicing impact.

3

Combination of one supporting pathogenic (PM2) and one supporting benign (BP4) criterion maps to VUS under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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: a 3' UTR substitution that leaves the stop codon and reading frame intact, with no predicted splicing effect (SpliceAI max delta 0.007).	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	Not applicable: this variant produces no amino acid change (p.?), and PS1 requires an established pathogenic change at the same position.
PS2	Not assessed	Not assessed: no de novo observation or parental testing results were available to establish the variant arose spontaneously.
PS3	Not assessed	Not assessed: no validated functional assay data (e.g., splicing reporter or mRNA stability studies) were available for this variant.
PS4	Not assessed	Not assessed: no affected case series or case-control enrichment data were available.
PM1	N/A	Not applicable: the variant lies in the 3' UTR, not in a protein domain or mutational hotspot.
PM2	Met	Met (supporting): absent from gnomAD v2.1 and seen once in 1,609,556 gnomAD v4.1 alleles (AF ~6.2e-07), far below the 0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no data showed the variant in trans with a pathogenic allele, so recessive-disease phase could not be evaluated.
PM4	N/A	Not applicable: the 3' UTR substitution does not alter the stop codon or protein length (p.?).	pvs1_variant_assessment
PM5	N/A	Not applicable: no amino acid substitution occurs, so there is no residue change to compare with known pathogenic missense variants.
PM6	Not assessed	Not assessed: no unconfirmed de novo observation or parental genotypes were documented.
PP1	Not assessed	Not assessed: no familial segregation or co-segregation data were available.
PP2	N/A	Not applicable: PP2 concerns missense variants, and this is a 3' UTR substitution with no amino acid change.
PP3	Not met	Not met: SpliceAI predicts no splicing impact (max delta 0.007) versus the >0.2 threshold required for PP3.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-specific testing context was supplied.
PP5	Not met	Not met: no ClinVar expert-panel pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: allele frequency 6.2e-07 (1/1,609,556) is far below the population frequency expected for a benign variant.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: the observed allele frequency (6.2e-07) shows no excess incompatible with disease causality.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no evidence showed the single gnomAD carrier is a phenotyped healthy adult.	gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal activity were available.
BS4	Not assessed	Not assessed: no tested unaffected relatives or non-segregation data were documented.
BP1	N/A	Not applicable: BP1 addresses missense variants, and this variant causes no amino acid change.
BP2	Not assessed	Not assessed: no family observations, second pathogenic variant, or phase information were available.
BP3	N/A	Not applicable: BP3 concerns in-frame indels in repetitive regions, and this is a single-nucleotide 3' UTR substitution.	pvs1_variant_assessment
BP4	Met	Met (supporting): SpliceAI max delta 0.007, well below the <0.1 threshold, indicating no predicted splicing impact.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular diagnosis or phenotype data were available to establish another cause.
BP6	Not met	Not met: no ClinVar expert-panel benign or likely benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 addresses synonymous coding variants, and this is a 3' UTR substitution.

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.