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RB1
Final classification
VUS
PM2BP4
RB1
c.1390-17T>A
p.?
unknown · exon 14i
Gene context NCBI Gene ↗ OncoKB ↗

RB1 encodes a protein that acts as a key brake on cell division: in its active form it blocks cells from moving from the G1 into the S phase of the cell cycle, and it also helps maintain the structure of packaged DNA in the nucleus. It was the first tumor suppressor gene identified. Loss of RB1 function removes this brake, leading to uncontrolled cell growth and contributing to many cancers, including retinoblastoma (a childhood eye cancer), bladder cancer, osteogenic sarcoma, and cancers of the lung, breast, and prostate. Inherited changes in RB1 predispose children to retinoblastoma and adults to sarcomas and other tumors.

This variant

RB1 is a tumor suppressor whose loss of function predisposes to retinoblastoma and other cancers. This deep intronic variant is extremely rare and predicted not to disrupt splicing, but no functional or case-level evidence establishes its effect on RB1 function, so it remains a variant of uncertain significance.

Transcript
NM_000321.3
HGVS · transcript:coding
NM_000321.3:c.1390-17T>A
GRCh38
chr13:48380036 T>A
GRCh37
chr13:48954172 T>A
Basis VUS: no RB1-specific VCEP framework exists, so generic ACMG/AMP 2015 rules applied, and the combination of PM2 (supporting) plus BP4 (supporting) meets no pathogenic or benign threshold. ▾
VUS: no RB1-specific VCEP framework exists, so generic ACMG/AMP 2015 rules applied, and the combination of PM2 (supporting) plus BP4 (supporting) meets no pathogenic or benign threshold.
Classification rationale
PM2 BP4 VUS
RB1 c.1390-17T>A unknown · exon 14i

PM2 (Supporting): variant is very rare in population databases (gnomAD v4.1 AF 0.01073%; no homozygotes). BP4 (Supporting): SpliceAI max delta 0.024 is below the <0.1 threshold, predicting no significant splice impact. Synthesis: PM2 and BP4 at supporting strength satisfy no ACMG/AMP 2015 pathogenic or benign combination rule, so the variant is classified as VUS.

PM2 + BP4 → VUS
Gene diagram · NM_000321.3 · variants mapped to exon structure
RB1 NM_000321.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (supporting): very rare in population databases, gnomAD v4.1 AF 0.01073% with no homozygotes.
gnomAD v4.1: 137/1,277,350 alleles, AF 0.000107253 (0.01073%), 0 homozygotes; maximum broad-population AF 0.000279174 (0.02792%).gnomAD v2.1: 24/142,264 alleles, AF 0.0001687 (0.01687%), 0 homozygotes; maximum broad-population AF 0.000269179 (0.02692%).gnomAD-Canada: 8/18,356 alleles, AF 0.000435825 (0.04358%), 0 homozygotes; the dataset flags the queried region as low complexity, so the Canada result is considered alongside the much larger gnomAD datasets rather than used alone.
gnomad_canada ↗gnomad_v4 ↗gnomad_v2 ↗
✓
BP4 supporting Benign
Met (supporting): SpliceAI max delta 0.024, below the <0.1 BP4 threshold, predicting no splice impact.
SpliceAI Lookup (source_registry key 'spliceai') for NM_000321.3:c.1390-17T>A: max_delta_score=0.024, all component deltas (DS_AG=0.001, DS_AL=0.019, DS_DG=0.005, DS_DL=0.024) well below 0.1 -- 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).'Generic ACMG in-silico calibration rule: SpliceAI max delta < 0.1 -> BP4 (supporting) for intronic/non-canonical-splice-position variants; 0.024 satisfies this threshold clearly.REVEL score not available (revel.found=false, score=null) and BayesDel score not available (bayesdel.found=false, score=null) in prefetch data; not applicable to this intronic variant's assessment path in any case, and BayesDel lacks a verified published threshold for this pipeline.
spliceai ↗
Assessed · not applied · 5 not met · 12 not assessed
Pathogenic
PS2 Not assessed: no confirmed de novo occurrence with parental testing and parentage confirmation was documented.
PS3 Not assessed: no functional or splicing assay data for this variant was available.
PS4 Not assessed: no case-control or enrichment data for this variant was retrieved.
PM3 Not assessed: no evidence establishes this variant in trans with a pathogenic RB1 variant.
PM6 Not assessed: no presumed de novo occurrence of this variant in an affected individual was documented.
PP1 Not assessed: no segregation data on affected or unaffected relatives was available.
PP3 Not met: SpliceAI max delta 0.024 versus the >0.2 PP3 threshold.
PP4 Not assessed: no patient phenotype, age of onset, or family history data was supplied.
PP5 Not met: ClinVar has no expert-panel submission for this variant.
Benign
BA1 Not met: highest population frequency 0.05987% versus the >1% BA1 threshold.
BS1 Not met: highest population frequency 0.05987% versus the >0.3% BS1 threshold.
BS2 Not assessed: no homozygotes observed, but no healthy-adult cohort data demonstrating unaffected carriers either.
BS3 Not assessed: no functional assay data demonstrating normal, no-effect function for this variant.
BS4 Not assessed: no unaffected-carrier or non-segregation observations were documented.
BP2 Not assessed: no phase or genotype data to establish trans or cis configuration with a pathogenic variant.
BP5 Not assessed: no carrier with an independently established alternate molecular diagnosis was found.
BP6 Not met: only non-expert ClinVar submissions exist, with no expert-panel assertion.
N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000107253; MAF= 0.01073%, 137/1277350 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000279174; MAF= 0.02792%, 1/3582 alleles, homozygotes = 0); grpmax FAF= 9.803e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.0001687; MAF= 0.01687%, 24/142264 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000269179; MAF= 0.02692%, 4/14860 alleles, homozygotes = 0); grpmax FAF= 0.00016271.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00043582479843103073, 8/18356 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.011% · 137 / 1,277,350
0 hom · FAF 0.0098%
Middle Eastern
1 / 3,582
0.028%
East Asian
5 / 37,112
0.013%
African/African American
8 / 65,108
0.012%
European (non-Finnish)
109 / 941,478
0.012%
Remaining individuals
5 / 49,136
0.01%
South Asian
6 / 66,996
0.009%
Admixed American
3 / 36,898
0.0081%
+ 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)
gnomAD v2.1
0.017% · 24 / 142,264
0 hom · FAF 0.016%
African/African American
4 / 14,860
0.027%
European (non-Finnish)
14 / 61,968
0.023%
Admixed American
2 / 12,902
0.016%
South Asian
2 / 16,552
0.012%
East Asian
1 / 8,986
0.011%
European (Finnish)
1 / 17,174
0.0058%
+ 2 not observed (Ashkenazi Jewish, Remaining individuals)
gnomAD Canada 🇨🇦
0.044% · 8 / 18,356
0 hom · FAF 0.028%
⚠ LCR
Middle Eastern
1 / 144
0.69%
European (non-Finnish)
7 / 11,692
0.06%
+ 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 194470)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Triaged references · 5 PMIDs not cited in assessment
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR
34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
26140447 ↗ Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. CLINVAR