Classification rationale

BP4 VUS

RB1 c.1390-17T>A unknown · exon 14i

BP4 (Supporting): SpliceAI max delta 0.024, below the 0.1 threshold - the intronic variant is not predicted to disrupt splicing. Overall: VUS - under generic ACMG/AMP 2015 rules, a single supporting benign criterion does not reach Likely Benign.

BP4 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000321.3 · variants mapped to exon structure

RB1 NM_000321.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 20 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.024 is below the 0.1 BP4 threshold, predicting no splice disruption.

SpliceAI Lookup for NM_000321.3:c.1390-17T>A reports maximum delta 0.024 (DS_AG 0.001, DS_AL 0.019, DS_DG 0.005, DS_DL 0.024).Generic ACMG operating rules direct intronic non-canonical splice-position variants to one SpliceAI-based PP3/BP4 pathway and assign BP4 supporting for maximum delta below 0.1.Walker et al., 2023, Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing (PMID:37352859), calibrated SpliceAI >=0.2 for PP3 and <=0.1 for BP4 for variants outside donor/acceptor ±1,2 positions.

spliceai ↗

Assessed · not applied · 8 not met · 12 not assessed

Pathogenic

PVS1 Not met: this intronic variant lies 17 bases upstream of the exon boundary with no predicted null consequence (SpliceAI max delta 0.024).

PS2 Not assessed: no proband phenotype, parental genotypes, or validated de novo status was available to evaluate PS2.

PS3 Not assessed: no variant-specific functional assay was available; the SpliceAI result is computational prediction only.

PS4 Not assessed: no case-control or cohort-enrichment evidence for this exact variant was available.

PM2 Not met: the variant is present in gnomAD v2.1, v4.1, and gnomAD-Canada, so it is not absent from population databases.

PM4 Not met: this intronic single-nucleotide variant produces no protein-length change (p.?), unlike the in-frame indels PM4 targets.

PM6 Not assessed: no case report or family study established the variant as apparently de novo.

PP1 Not assessed: no affected or unaffected relatives with informative segregation were documented.

PP3 Not met: SpliceAI max delta 0.024 falls below the 0.2 PP3 threshold.

PP4 Not assessed: no proband phenotype indicating high specificity for RB1-related disease was available.

PP5 Not met: ClinVar holds only non-expert single-submitter Uncertain and Likely benign assertions, with no expert-panel submission.

Benign

BA1 Not met: maximum observed allele frequency is 0.04358% (gnomAD-Canada), far below the 5% BA1 threshold.

BS1 Not assessed: no RB1-specific or disease-derived maximum credible allele frequency was available to test against the observed 0.04358%.

BS2 Not assessed: no homozygotes are reported, and population records do not confirm carriers are healthy adults.

BS3 Not assessed: no variant-specific functional assay demonstrating preserved RB1 function was available.

BS4 Not assessed: no confirmed non-carrier relatives were documented for non-segregation evaluation.

BP2 Not assessed: no second RB1 pathogenic variant or phase information was available for the trans/cis evaluation.

BP3 Not met: the variant is an intronic SNV, not an in-frame indel in a repetitive region.

BP5 Not assessed: no affected individual with this variant plus a separate explanatory molecular diagnosis was documented.

BP6 Not met: ClinVar shows no expert-panel submission; the non-expert Likely benign assertion alone cannot trigger BP6.

N/A · 7 PS1 · PM1 · PM3 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

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

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 194470)

ClinVar ↗

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

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

31275557 ↗ Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. CLINVAR

20301625 ↗ Retinoblastoma. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

35802134 ↗ ACMG SF v3.1 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

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