About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1383A>G, p.(Gln461=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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 ClinGen BRAF VCEP v2.3.0. 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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant exceeds the BRAF RASopathy BA1 population threshold. In gnomAD v2.1, the overall allele frequency is 0.12339% (349/282834 alleles) and the grpmax filtering allele frequency is 1.2192%, both above the BA1 threshold of 0.05%.
BP4Supporting
BP4 · supporting
Computational evidence does not suggest a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the BP4 threshold of 0.3.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP4 supporting, BP6 supporting benign; maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1,206 / 1,614,110 alleles
gnomAD v4.1: 1,206 / 1,614,110 alleles. Recorded AF 0.000747161. Recorded homozygote count 12.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00123394; MAF= 0.12339%, 349/282834 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0130146; MAF= 1.30146%, 325/24972 alleles, homozygotes = 3); grpmax FAF= 0.012192.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRAF VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BRAF c.1383A>G (p.Gln461=, p.Q461=) variant has been reported in ClinVar as benign, including a benign expert-panel assertion from the ClinGen RASopathy Variant Curation Expert Panel, and it has not been established as a statistically significant hotspot at codon 461.
This variant is present in gnomAD v2.1 at 0.12339% overall (349/282834 alleles; 3 homozygotes), with an African/African American frequency of 1.30146% and grpmax filtering allele frequency of 1.2192%, which is above the BRAF RASopathy BA1 threshold of 0.05%.
Computational data do not suggest a harmful effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084.
No criteria match.
Met · 3
BA1 Stand aloneThis variant exceeds the BRAF RASopathy BA1 population threshold. In gnomAD v2.1, the overall allele frequency is 0.12339% (349/282834 alleles) and the grpmax filtering allele frequency is 1.2192%, both above the BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 total AF 0.12339%.
- gnomAD v2.1 grpmax FAF 1.2192%.
- BA1 threshold is filtering AF ≥0.05%.
Sources
BP4 SupportingComputational evidence does not suggest a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the BP4 threshold of 0.3. Details ▾Hide ▴
Rule
REVEL ≤0.3 for missense or negligible predicted splice effect.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.084.
- BP4 threshold is REVEL ≤0.3 or negligible predicted splice effect.
Sources
Not met · 3 · evaluated, threshold not reached
PM1 Although codon 461 falls within the BRAF P-loop region listed by the RASopathy VCEP, this variant is synonymous and Cancer Hotspots did not establish Q461 as a statistically significant hotspot, so PM1 is not applied. Details ▾Hide ▴
Rule
Critical domain or hotspot evidence without benign variation.
Evidence considered
- PM1 domain list includes the P-loop (AA 459-474).
- Cancer Hotspots review reported no hotspot row for BRAF Q461.
Sources
PM2 This variant is present in gnomAD and therefore is not absent from controls, so PM2 is not met. Details ▾Hide ▴
Rule
Variant must be absent from gnomAD.
Evidence considered
- gnomAD v2.1 total AF 0.12339% (349/282834 alleles)
- 3 homozygotes.
Sources
PP3 Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the PP3 threshold of 0.7. Details ▾Hide ▴
Rule
REVEL ≥0.7 for missense or predicted splice effect matching disease mechanism.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.084.
Sources
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo observation with parental testing and phenotype-based point scoring was identified for this variant. Details ▾Hide ▴
Rule
Point-based confirmed de novo criterion.
Evidence considered
- RASopathy VCEP uses point-based de novo scoring for PS2.
Still missing
- Case-level de novo data with maternity and paternity confirmation were not identified.
Sources
PS3 No approved functional study for this exact variant was identified in the reviewed RASopathy VCEP functional materials. Details ▾Hide ▴
Rule
Requires approved functional assay evidence for a damaging effect.
Evidence considered
- RASopathy VCEP functional studies summary lists approved assay types
- but no exact study for p.(Q461=) was identified.
Still missing
- Exact-variant functional assay data were not identified.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No affected-individual enrichment or point-based case evidence was identified to support PS4 for this variant. Details ▾Hide ▴
PM6 No presumed de novo observation without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Point-based assumed de novo criterion.
Evidence considered
- RASopathy VCEP uses point-based PM6 scoring when de novo evidence is incomplete.
Still missing
- Case-level presumed de novo data were not identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Segregation criterion.
Evidence considered
- PP1 requires segregation evidence with informative meioses.
Still missing
- Informative meioses were not identified.
Sources
BS1 The observed population frequency also exceeds the BS1 threshold, but BA1 is already met and BS1 is not additionally applied to avoid double counting the same population evidence. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 1.2192%.
- BS1 threshold is filtering AF ≥0.025%.
Sources
BS2 Population data show 3 homozygotes in gnomAD, but BS2 in this framework requires phenotype-aware unaffected observations, which were not identified for this variant. Details ▾Hide ▴
Rule
Point-based unaffected observation criterion.
Evidence considered
- gnomAD v2.1 includes 3 homozygotes.
- RASopathy VCEP uses point-based BS2 scoring based on healthy or apparently unaffected individuals.
Still missing
- No phenotype-based unaffected carrier observations were identified.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
Lack of segregation criterion.
Evidence considered
- BS4 requires informative non-segregation evidence.
Still missing
- No informative family data showing lack of segregation were identified.
Sources
BP2 No phase data or alternative molecular explanation in the same gene were identified for this variant. Details ▾Hide ▴
Rule
Point-based alternative molecular cause in same gene.
Evidence considered
- BP2 is point-based in this framework.
Still missing
- No scored BP2 case observations were identified.
Sources
BP5 No alternative molecular diagnosis in another gene or fully explanatory non-RASopathy diagnosis was identified for this variant. Details ▾Hide ▴
Rule
Point-based alternative molecular cause in another gene.
Evidence considered
- BP5 is point-based in this framework.
Still missing
- No scored BP5 case observations were identified.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, but no conservation evidence was identified to confirm the full BP7 requirement that the affected nucleotide is not highly conserved. Details ▾Hide ▴
Rule
Synonymous variant with no predicted splice effect and low conservation.
Evidence considered
- SpliceAI max delta score 0.01.
- BP7 requires no predicted splice effect and a nucleotide that is not highly conserved.
Still missing
- No conservation evidence for the altered nucleotide was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis synonymous variant does not fall into the null-variant categories used for PVS1, and the generic PVS1 assessment did not support PVS1 application. Details ▾Hide ▴
Rule
PVS1 not applicable for this variant type.
Evidence considered
- BRAF RASopathy VCEP marks PVS1 as not applicable for this variant context.
- Generic PVS1 scaffold states the variant is not a nonsense
- frameshift
- or canonical splice-site change.
Sources
PS1 N/APS1 requires a previously established pathogenic amino acid substitution, but this variant is synonymous and does not change the encoded amino acid. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Protein consequence is p.(Gln461=) / p.(Q461=).
- PS1 is defined for the same amino acid change as a known pathogenic variant.
Sources
PM3 N/APM3 is not applicable in this RASopathy framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 applies to in-frame insertions/deletions or stop-loss variants, and this variant is a synonymous substitution. Details ▾Hide ▴
Rule
Protein length change criterion.
Evidence considered
- PM4 is defined for protein length changes.
- Variant consequence is synonymous.
Sources
PM5 N/AThe RASopathy VCEP uses classic same-residue missense PM5 logic, but this variant is not missense-like, so PM5 is not applicable. Details ▾Hide ▴
Rule
Classic same-residue missense comparator rule.
Evidence considered
- PM5 comparator review found the variant was not eligible for classic same-residue missense PM5 search.
Sources
cspec ↗pm5_candidates
PP2 N/APP2 is a missense criterion, and this variant is synonymous. Details ▾Hide ▴
Rule
Missense-only criterion.
Evidence considered
- PP2 applies to missense variants.
- Variant consequence is synonymous.
Sources
PP4 N/APP4 is not applicable in this RASopathy framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP marks PP5 as not applicable.
Sources
BS3 N/ABS3 is not applicable in this RASopathy framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP marks BS3 as not applicable.
Sources
BP1 N/ABP1 in this framework is used for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanism, and this variant is not truncating. Details ▾Hide ▴
Rule
Truncating variant criterion in GOF disease genes.
Evidence considered
- BP1 is specified for truncating variants in this RASopathy framework.
- Variant consequence is synonymous.
Sources
BP3 N/ABP3 is not applicable in this RASopathy framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP marks BP3 as not applicable.
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1383A>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Gln461=)
- GRCh38
- chr7:140781625 T>C
- GRCh37
- chr7:140481425 T>C
Gene diagram
Every interpreted variant in BRAF, mapped onto the exon structure of NM_001354609.1. Select a row to find it on the plot.
BRAFNM_001354609.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRAF
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1,206 / 1,614,110 alleles
AF 0.000747 · 12 homozygotes · FAF 0.0127
gnomAD v2.1
349 / 282,834 alleles
AF 0.00123 · 3 homozygotes · FAF 0.0122
By genetic ancestry
gnomAD v4.1
AF 0.00075 · 1206 / 1,614,110 alleles · 12 hom · FAF 0.013
| African/African American1007 / 75,040 | 0.0139 hom |
| Remaining individuals62 / 62,508 | 0.000991 hom |
| Middle Eastern6 / 6,062 | 0.00099 |
| Admixed American39 / 60,014 | 0.000651 hom |
| South Asian13 / 91,084 | 0.000141 hom |
| European (non-Finnish)79 / 1,180,000 | 6.7e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0012 · 349 / 282,834 alleles · 3 hom · FAF 0.012
| African/African American325 / 24,972 | 0.0133 hom |
| Remaining individuals2 / 7,228 | 0.00028 |
| Admixed American7 / 35,432 | 0.0002 |
| South Asian5 / 30,612 | 0.00016 |
| European (non-Finnish)10 / 129,156 | 7.7e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000747161; MAF= 0.07472%, 1206/1614110 alleles, homozygotes = 12) and has highest observed frequency in the African/African American population (AF= 0.0134195; MAF= 1.34195%, 1007/75040 alleles, homozygotes = 9); grpmax FAF= 0.0127315.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00123394; MAF= 0.12339%, 349/282834 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0130146; MAF= 1.30146%, 325/24972 alleles, homozygotes = 3); grpmax FAF= 0.012192.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational evidence does not suggest a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the BP4 threshold of 0.3. Details ▾Hide ▴
Rule
REVEL ≤0.3 for missense or negligible predicted splice effect.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.084.
- BP4 threshold is REVEL ≤0.3 or negligible predicted splice effect.
Sources
PP3 Computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the available REVEL score is 0.084, which is below the PP3 threshold of 0.7. Details ▾Hide ▴
Rule
REVEL ≥0.7 for missense or predicted splice effect matching disease mechanism.
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.084.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, but no conservation evidence was identified to confirm the full BP7 requirement that the affected nucleotide is not highly conserved. Details ▾Hide ▴
Rule
Synonymous variant with no predicted splice effect and low conservation.
Evidence considered
- SpliceAI max delta score 0.01.
- BP7 requires no predicted splice effect and a nucleotide that is not highly conserved.
Still missing
- No conservation evidence for the altered nucleotide was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.084.
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
1,206 / 1,614,110 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243119
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/40363/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140481425-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140781625-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/Q461=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=189859988
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000747161; MAF= 0.07472%, 1206/1614110 alleles, homozygotes = 12) and has highest observed frequency in the African/African American population (AF= 0.0134195; MAF= 1.34195%, 1007/75040 alleles, homozygotes = 9); grpmax FAF= 0.0127315.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00123394; MAF= 0.12339%, 349/282834 alleles, homozygotes = 3) and has highest observed frequency in the African/African American population (AF= 0.0130146; MAF= 1.30146%, 325/24972 alleles, homozygotes = 3); grpmax FAF= 0.012192.
ClinVar
This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40363)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.084.
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104607983, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.