About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.483G>C, p.(Leu161=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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
BS1Strong
BS1 · strong
The BRAF VCEP BS1 threshold is gnomAD filtering allele frequency >=0.025%. This variant exceeds that threshold in both population datasets, with grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1.
BP4Supporting
BP4 · supporting
Available computational evidence supports no functional impact on splicing. SpliceAI predicts no significant splice effect for this synonymous variant, with a maximum delta score of 0.02.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.
Recorded classification: Likely 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 Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP4 supporting, BP6 supporting benign; maps to Likely 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
48 / 1,614,116 alleles
gnomAD v4.1: 48 / 1,614,116 alleles. Recorded AF 2.97376e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65731e-05; MAF= 0.00566%, 16/282820 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000600769; MAF= 0.06008%, 15/24968 alleles, homozygotes = 0); grpmax FAF= 0.00037921.
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 · 4 not met · 10 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.483G>C (p.Leu161=) variant has not been identified as a statistically significant hotspot in Cancer Hotspots and has been reported in ClinVar as benign/likely benign, including a likely benign expert-panel classification.
This variant is present in gnomAD, with grpmax filtering allele frequency 0.03792% in v2.1 and 0.04133% in v4.1, which is above the BRAF VCEP BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.
In silico splice prediction does not support a deleterious effect, with SpliceAI showing a maximum delta score of 0.02 for this synonymous change.
No criteria match.
Met · 3
BS1 StrongThe BRAF VCEP BS1 threshold is gnomAD filtering allele frequency >=0.025%. This variant exceeds that threshold in both population datasets, with grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1. Details ▾Hide ▴
BP4 SupportingAvailable computational evidence supports no functional impact on splicing. SpliceAI predicts no significant splice effect for this synonymous variant, with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Sources
BP6 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PM1 This variant is in exon 3 at p.Leu161=, which is outside the BRAF VCEP-listed PM1 regions (exon 6, exon 11, P-loop amino acids 459-474, and CR3 activation segment amino acids 594-627). Cancer Hotspots also did not identify this site as a statistically significant hotspot. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]). Not applicable to specific amino acid residues (see PM5).
Sources
PM2 This variant is present in population databases and therefore is not absent from controls. In gnomAD v2.1 the total allele frequency is 0.00566% with grpmax FAF 0.03792%, and in gnomAD v4.1 the total allele frequency is 0.00297% with grpmax FAF 0.04133%. Details ▾Hide ▴
PP3 Available computational evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, which is below a level that would support PP3. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Sources
BA1 The BRAF VCEP BA1 threshold is gnomAD filtering allele frequency >=0.05%. This variant has grpmax FAF 0.03792% in gnomAD v2.1 and 0.04133% in gnomAD v4.1, both below the BA1 threshold. Details ▾Hide ▴
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Still missing
- No exact-variant trio data or confirmed parental testing was identified.
Sources
PS3 No approved functional study for this specific variant was identified to show a damaging effect on protein function or splicing. Details ▾Hide ▴
Still missing
- No variant-specific approved functional assay result was identified.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No affected-proband series or case-control enrichment data were identified for this variant. Details ▾Hide ▴
PM6 No presumed de novo occurrence with incomplete parental confirmation was identified for this variant. Details ▾Hide ▴
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
BS2 No data were identified showing this variant in well-phenotyped unaffected individuals sufficient for BS2 scoring. Details ▾Hide ▴
Still missing
- No unaffected-carrier evidence with point assignment was identified.
Sources
BS4 No nonsegregation data were identified for this variant. Details ▾Hide ▴
BP2 No evidence was identified that this variant occurs with an alternative molecular explanation in cis or trans sufficient for BP2 scoring. Details ▾Hide ▴
BP5 No evidence was identified for an alternative molecular cause of disease sufficient for BP5 scoring. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis or phenotype-discordant explanation was identified.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but no nucleotide conservation evidence was identified to satisfy the full BP7 rule. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Still missing
- No conservation evidence was identified for the altered nucleotide.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a synonymous substitution, and the BRAF RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this variant is not a nonsense, frameshift, or canonical +/-1,2 splice-site variant. Details ▾Hide ▴
PS1 N/AThis variant does not change the encoded amino acid and therefore does not meet the PS1 requirement for the same pathogenic amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Sources
PM3 N/APM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Sources
PM4 N/AThis variant is a single-nucleotide synonymous substitution and does not cause an in-frame protein length change or stop-loss event. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Sources
PM5 N/AThis variant does not alter the amino acid sequence, so the PM5 missense-at-same-codon rule does not apply. Details ▾Hide ▴
PP2 N/APP2 is a missense criterion, and this variant is synonymous. Details ▾Hide ▴
PP4 N/APP4 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
BS3 N/ABS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Sources
BP1 N/ABP1 in this framework applies to truncating loss-of-function variants in a gain-of-function disease setting, and this variant is not a truncating variant. Details ▾Hide ▴
Rule
Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant in genes without established LOF correlation to disease.
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.483G>C
- Protein (HGVS p.)
- NP_001341538.1:p.(Leu161=)
- GRCh38
- chr7:140834630 C>G
- GRCh37
- chr7:140534430 C>G
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRAF
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
48 / 1,614,116 alleles
AF 2.97e-05 · 0 homozygotes · FAF 0.000413
gnomAD v2.1
16 / 282,820 alleles
AF 5.66e-05 · 0 homozygotes · FAF 0.000379
By genetic ancestry
gnomAD v4.1
AF 3e-05 · 48 / 1,614,116 alleles · 0 hom · FAF 0.00041
| African/African American41 / 75,016 | 0.00055 |
| Remaining individuals5 / 62,510 | 8e-05 |
| Admixed American2 / 60,014 | 3.3e-05 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 5.7e-05 · 16 / 282,820 alleles · 0 hom · FAF 0.00038
| African/African American15 / 24,968 | 0.0006 |
| Remaining individuals1 / 7,222 | 0.00014 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.97376e-05; MAF= 0.00297%, 48/1614116 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00054655; MAF= 0.05466%, 41/75016 alleles, homozygotes = 0); grpmax FAF= 0.00041326.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65731e-05; MAF= 0.00566%, 16/282820 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000600769; MAF= 0.06008%, 15/24968 alleles, homozygotes = 0); grpmax FAF= 0.00037921.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable computational evidence supports no functional impact on splicing. SpliceAI predicts no significant splice effect for this synonymous variant, with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3. For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Sources
PP3 Available computational evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, which is below a level that would support PP3. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, but no nucleotide conservation evidence was identified to satisfy the full BP7 rule. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Still missing
- No conservation evidence was identified for the altered nucleotide.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
48 / 1,614,116 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/44826/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140534430-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140834630-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/BRAF/L161=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.483G%3EC
- 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= 2.97376e-05; MAF= 0.00297%, 48/1614116 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00054655; MAF= 0.05466%, 41/75016 alleles, homozygotes = 0); grpmax FAF= 0.00041326.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 5.65731e-05; MAF= 0.00566%, 16/282820 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000600769; MAF= 0.06008%, 15/24968 alleles, homozygotes = 0); grpmax FAF= 0.00037921.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.