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RB1c.743G>CUncertain significance
Print report
Variant interpretation report

RB1 c.743G>C, p.(Gly248Ala)

NM_000321.2:c.743G>C NP_000312.2:p.(Gly248Ala) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About RB1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with a population allele frequency of 0%. This meets the PM2 threshold for absence from large population databases (AF < 0.1% under non-VCEP generic ACMG rules).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious effect. REVEL score is 0.272 (benign range, below 0.5 threshold). BayesDel score is -0.129 (negative, benign prediction). SpliceAI max delta score is 0.01 (no splicing impact, well below 0.2). Three independent in silico predictors concur on a benign or non-deleterious prediction, satisfying BP4 at supporting benign strength.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung ca

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 19 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2 (moderate): The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, with an allele frequency of 0% in all queried population databases, supporting moderate evidence for pathogenicity.

BP1 (supporting benign): RB1 is a gene in which >80% of pathogenic germline variants are truncating, and missense variants account for only 9.2% of pathogenic variants (PMID:42461076). This missense variant occurs in a gene where the primary disease mechanism is loss of function through null alleles.

BP4 (supporting benign): Multiple lines of computational evidence — REVEL score 0.272, BayesDel score -0.129, and SpliceAI max delta 0.01 — converge on a non-deleterious prediction, providing supporting evidence against pathogenicity.

Classification: Uncertain Significance (VUS). There is conflicting evidence: PM2 (moderate pathogenicity) from complete absence in population databases is offset by BP1 (supporting benign) and BP4 (supporting benign). The two supporting benign criteria do not reach the 'likely benign' threshold in the presence of a moderate pathogenic criterion. Additional evidence — particularly functional studies, segregation data, or clinical case reports — is needed to resolve this variant's clinical significance.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with a population allele frequency of 0%. This meets the PM2 threshold for absence from large population databases (AF < 0.1% under non-VCEP generic ACMG rules). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent (AF = 0). gnomAD v4.1: absent (AF = 0). gnomAD-Canada v1.0: absent (AF = 0). Complete absence across all queried population databases.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect. REVEL score is 0.272 (benign range, below 0.5 threshold). BayesDel score is -0.129 (negative, benign prediction). SpliceAI max delta score is 0.01 (no splicing impact, well below 0.2). Three independent in silico predictors concur on a benign or non-deleterious prediction, satisfying BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.272 (benign). BayesDel: -0.129154 (benign). SpliceAI: max delta 0.01 (no splice impact). Three convergent benign predictions from independent computational methods.
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS1 No known pathogenic variant affecting the same amino acid (Gly248) via a different nucleotide change has been identified. The variant is absent from ClinVar and no literature reports a pathogenic comparator at this residue. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for this variant or any other variant at residue Gly248. PM5 candidate harvesting found zero same-residue comparator variants.
Sources
clinvar ↗pm5_candidates
PS2 No de novo data available; both paternal and maternal confirmation were not assessed. No family-based or parent-of-origin testing data are present for this case. Details ▾Hide ▴
Evidence considered
  • No parental genotype data
  • trio sequencing
  • or de novo confirmation studies available.
Still missing
  • Parental testing or de novo confirmation would be required to assess PS2.
PS3 No variant-specific functional data available. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence for G248A. No publication identified with experimental characterization of this variant or a systematically characterized range that includes residue 248. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No PMIDs identified with functional data for NM_000321.2:c.743G>C or a systematically assayed range encompassing Gly248.
Still missing
  • Functional characterization of p.Gly248Ala would be needed to assess PS3.
Sources
oncokb ↗
PS4 No case-control data or statistical enrichment data available for this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
  • No case-control studies
  • cohort frequency comparisons
  • or statistical enrichment analyses available for this variant.
Still missing
  • Case-control data or cohort enrichment statistics would be needed to assess PS4.
PM1 Residue Gly248 is located in the N-terminal region of RB1, outside the well-characterized Pocket A and Pocket B domains. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. Published RB1 variant landscape data (PMID:42461076) shows that pathogenic missense variants are concentrated in Pocket B, not the N-terminal region. The N-terminal domain accumulates primarily nonsense, not missense, pathogenic variants. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no significant hotspot at this residue. PMID:42461076: 'missense variants were concentrated in Pocket B' and 'nonsense variants predominated in the N-terminal
  • Pocket A
  • and C-terminal regions.' Position 248 lies in the N-terminal domain
  • where truncating rather than missense variants are the predominant pathogenic mechanism.
PM6 No de novo data available for this variant. No family-based studies or trio analyses have been performed. No literature reports a de novo occurrence of c.743G>C. Details ▾Hide ▴
Evidence considered
  • No de novo confirmation data
  • trio sequencing
  • or parental testing available.
Still missing
  • Parental testing or a confirmed de novo report in the literature would be needed to assess PM6.
PP1 No co-segregation data available. No family pedigree or segregation analysis has been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No co-segregation or family pedigree data available.
Still missing
  • Segregation analysis in affected families would be needed to assess PP1.
PP2 RB1 is a tumor suppressor gene where truncating variants (nonsense, frameshift, splice-site, large deletions) account for >80% of pathogenic germline variants (PMID:42461076). Missense variants comprise only 9.2% of pathogenic germline variants and are not a common disease mechanism for RB1. The variant does not meet the PP2 criterion requiring missense variants to be a common mechanism of disease in a gene with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • PMID:42461076: truncating germline variants accounted for >80% of variants
  • missense variants comprised 9.2%. Missense pathogenic variants are concentrated in Pocket B
  • not the N-terminal region where Gly248 resides.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.272 (below the commonly used 0.5 threshold for pathogenicity). BayesDel score is -0.129 (negative, indicating benign). SpliceAI max delta score is 0.01 (no predicted splicing impact). The weight of computational evidence does not support PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.272 (benign range
  • below 0.5 threshold). BayesDel: -0.129154 (negative score
  • benign prediction). SpliceAI: max delta 0.01 (no splice impact
  • well below 0.2 threshold). All three in silico predictors converge on a non-deleterious prediction.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data are available. The variant was assessed in isolation without clinical context; PP4 requires a highly specific phenotype or family history for the disease. Details ▾Hide ▴
Evidence considered
  • No patient-specific clinical data
  • phenotype
  • or family history available for this case.
Still missing
  • Patient phenotype and family history data would be needed to assess PP4.
PP5 This variant is absent from ClinVar. PP5 requires a reputable source (e.g., ClinVar expert panel) to have classified the variant as pathogenic; no such classification exists. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries found for NM_000321.2:c.743G>C. Zero submissions
  • zero classifications.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0% does not meet the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 0. gnomAD v4.1: AF = 0. Both well below the BA1 threshold of >1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0% does not meet the BS1 threshold of >0.3% under generic non-VCEP rules. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 0. gnomAD v4.1: AF = 0. Both well below the BS1 threshold of >0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation data in healthy adult controls are available. BS2 requires the variant to be observed in a healthy adult individual for a disorder with full penetrance expected at an early age, which cannot be assessed without such data. Details ▾Hide ▴
Evidence considered
  • No data on observation of this variant in healthy adult controls.
Still missing
  • Observation in healthy adult controls would be needed to assess BS2 for this dominant
  • early-onset disorder.
BS3 No well-established functional studies demonstrating no deleterious effect are available for this variant. OncoKB reports Unknown Oncogenic Effect. No published experimental data characterize the functional consequence of p.Gly248Ala. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect with no variant-specific functional data. No publications with functional characterization of p.Gly248Ala.
Still missing
  • Functional studies demonstrating a benign effect of p.Gly248Ala would be needed to assess BS3.
Sources
oncokb ↗
BS4 No segregation data available. BS4 requires lack of co-segregation with disease in affected family members; no family studies have been performed for this variant. Details ▾Hide ▴
Evidence considered
  • No co-segregation or family pedigree data available.
Still missing
  • Segregation analysis would be needed to assess BS4.
BP2 No data on whether this variant has been observed in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant in a recessive disorder or in cis with a pathogenic variant in a dominant disorder, which cannot be assessed without phase data. Details ▾Hide ▴
Evidence considered
  • No phase data or co-occurrence data with other RB1 variants available.
Still missing
  • Phase data or co-occurrence data with known pathogenic RB1 variants would be needed.
BP5 This variant is absent from ClinVar. BP5 requires a reputable source to have classified the variant as benign; no such classification exists. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries found. No reputable source has classified this variant as benign.
Sources
clinvar ↗
BP6 This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign; no such classification exists. Details ▾Hide ▴
Evidence considered
  • ClinVar: no entries found. No reputable source has classified this variant as benign.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

BP1 RB1 is a gene in which >80% of pathogenic germline variants are truncating (nonsense, frameshift, splice-site, large deletions). Missense variants account for only 9.2% of pathogenic variants (PMID:42461076). The variant c.743G>C is a missense change in a gene where the primary disease mechanism is loss of function through truncating variants, satisfying BP1 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • PMID:42461076: >80% truncating variants among germline RB1 pathogenic variants. Missense variants comprise only 9.2%. RB1 disease mechanism is primarily loss of function via null alleles.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.743G>C, p.Gly248Ala); does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution in exon 8
  • the generic PVS1 decision framework explicitly excludes missense variants from default null-variant consideration.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo comparator variants at the same amino acid residue (Gly248) with a different amino acid change were identified. PM5 candidate harvesting returned zero same-residue candidates, and ClinVar contains no entries for any variant at residue 248. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search yielded zero same-residue comparator variants. ClinVar has no entries at Gly248.
Sources
pm5_candidatesclinvar ↗
BP7 N/AThis is a missense variant (c.743G>C, p.Gly248Ala), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not synonymous. BP7 is restricted to synonymous variants.
PS5 N/APS5 is only applicable for recessive disorders (biallelic variant in trans with a known pathogenic variant). RB1-associated disease follows autosomal dominant inheritance. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RB1
Transcript
NM_000321.2
Coding (HGVS c.)
NM_000321.2:c.743G>C
Protein (HGVS p.)
NP_000312.2:p.(Gly248Ala)
GRCh38
chr13:48362839 G>C
GRCh37
chr13:48936975 G>C

Gene diagram

Every interpreted variant in RB1, mapped onto the exon structure of NM_000321.2. Select a row to find it on the plot.

RB1NM_000321.2
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +6 bp
0.000
SpliceAI acceptor gainat +19 bp
0.010
SpliceAI donor lossat +23 bp
0.000
SpliceAI donor gainat +19 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.272
BayesDel
-0.129

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect. REVEL score is 0.272 (benign range, below 0.5 threshold). BayesDel score is -0.129 (negative, benign prediction). SpliceAI max delta score is 0.01 (no splicing impact, well below 0.2). Three independent in silico predictors concur on a benign or non-deleterious prediction, satisfying BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.272 (benign). BayesDel: -0.129154 (benign). SpliceAI: max delta 0.01 (no splice impact). Three convergent benign predictions from independent computational methods.
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.272 (below the commonly used 0.5 threshold for pathogenicity). BayesDel score is -0.129 (negative, indicating benign). SpliceAI max delta score is 0.01 (no predicted splicing impact). The weight of computational evidence does not support PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.272 (benign range
  • below 0.5 threshold). BayesDel: -0.129154 (negative score
  • benign prediction). SpliceAI: max delta 0.01 (no splice impact
  • well below 0.2 threshold). All three in silico predictors converge on a non-deleterious prediction.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.743G>C, p.Gly248Ala), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not synonymous. BP7 is restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.272. BayesDel score = -0.129154.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.272. BayesDel score = -0.129154.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RB1, a regulator of the cell cycle, is inactivated by mutation, deletion or allelic loss in various cancer types, including retinoblastoma and lung ca

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.