About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.2127+3A>G, p.?
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: 5
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 5
BA1Stand alone
BA1 · stand alone
This variant exceeds the BRAF RASopathy VCEP BA1 population threshold of filtering allele frequency at or above 0.05%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BA1 threshold.
BS1Strong
BS1 · strong
This variant exceeds the BRAF RASopathy VCEP BS1 population threshold of filtering allele frequency at or above 0.025%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BS1 threshold.
BP4Supporting
BP4 · supporting
Available computational evidence predicts little or no splice effect. SpliceAI shows a maximum delta score of 0.16, which does not support a meaningful abnormal splicing outcome, so the in silico evidence supports BP4 for a splice-region variant in this VCEP framework.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
BP7Supporting
BP7 · supporting
This variant is a noncanonical intronic splice-region change at +3, and the BRAF RASopathy VCEP allows BP7 for intronic positions outside canonical splice sites when used with BP4. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.16, which supports BP7.
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, BS1 strong, BP4 supporting, BP6 supporting benign, BP7 supporting; 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
152 / 1,612,098 alleles
gnomAD v4.1: 152 / 1,612,098 alleles. Recorded AF 9.42871e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000176897; MAF= 0.01769%, 50/282650 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0017222; MAF= 0.17222%, 43/24968 alleles, homozygotes = 1); grpmax FAF= 0.0015909.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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: 5 met · 2 not met · 9 not assessed · 12 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.2127+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as benign or likely benign, including a benign expert-panel classification.
This variant is present in population databases at a frequency above the BRAF RASopathy VCEP benign thresholds, with grpmax filtering allele frequencies of 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1.
SpliceAI predicts no significant splice impact for this intronic +3 variant, with a maximum delta score of 0.16, which does not support a deleterious splicing effect and is consistent with BP4 and BP7 in this framework.
No criteria match.
Met · 5
BA1 Stand aloneThis variant exceeds the BRAF RASopathy VCEP BA1 population threshold of filtering allele frequency at or above 0.05%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BA1 threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0015909 (0.15909%).
- gnomAD v4.1 grpmax FAF 0.00137943 (0.137943%).
Sources
BS1 StrongThis variant exceeds the BRAF RASopathy VCEP BS1 population threshold of filtering allele frequency at or above 0.025%. The highest observed filtering allele frequency is 0.15909% in gnomAD v2.1 and 0.137943% in gnomAD v4.1, both above the BS1 threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0015909 (0.15909%).
- gnomAD v4.1 grpmax FAF 0.00137943 (0.137943%).
Sources
BP4 SupportingAvailable computational evidence predicts little or no splice effect. SpliceAI shows a maximum delta score of 0.16, which does not support a meaningful abnormal splicing outcome, so the in silico evidence supports BP4 for a splice-region variant in this VCEP framework. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.16
- DS_DL 0.01.
- SpliceAI max delta score 0.16.
Sources
BP6 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign. Details ▾Hide ▴
BP7 SupportingThis variant is a noncanonical intronic splice-region change at +3, and the BRAF RASopathy VCEP allows BP7 for intronic positions outside canonical splice sites when used with BP4. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.16, which supports BP7. Details ▾Hide ▴
Rule
Applicable for intronic positions except canonical splice sites and used in conjunction with BP4 when splicing impact is not predicted.
Evidence considered
- Variant position is +3 and therefore outside the canonical ±1
- 2 splice site.
- SpliceAI max delta score 0.16.
Sources
Not met · 2 · evaluated, threshold not reached
PM2 PM2 requires absence from gnomAD. This variant is present in gnomAD v2.1 at 50/282650 alleles (AF 0.01769%) and in gnomAD v4.1 at 152/1612098 alleles (AF 0.00943%), so it does not meet PM2. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.000176897.
- gnomAD v4.1 total AF 0.0000942871.
Sources
PP3 For splicing impact, PP3 requires computational evidence supporting an abnormal outcome consistent with disease mechanism. SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.16, so available in silico evidence does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_DG 0.16.
- SpliceAI max delta score 0.16.
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity confirmation was identified for this variant. Available evidence does not provide the point-based de novo data required for PS2 under the RASopathy VCEP framework. Details ▾Hide ▴
Rule
Point-based de novo evidence is required.
Evidence considered
- ClinVar record does not provide usable PS2-level de novo evidence in the reviewed materials.
Still missing
- No parental testing details were identified.
- No confirmed de novo case report was identified for this exact variant.
Sources
PS3 No approved functional or RNA study was identified for this exact variant showing abnormal splicing or another damaging effect. Available evidence is insufficient to apply PS3. Details ▾Hide ▴
Rule
One approved assay supports PS3_Supporting; two or more different approved assays support PS3_Moderate.
Evidence considered
- No exact-variant functional study was identified in the reviewed materials.
Still missing
- No RT-PCR
- minigene
- or other variant-specific RNA study was identified.
- No approved functional assay result for this exact variant was identified.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 This variant is reported in ClinVar, but no verified affected-case count, enrichment analysis, or VCEP point total was identified for this exact variant. Available evidence does not support applying PS4. Details ▾Hide ▴
Rule
Point-based affected observations are required.
Evidence considered
- ClinVar shows benign and likely benign submissions
- including expert-panel review
- but no usable PS4 point total.
Still missing
- No exact-variant affected-case count was identified.
- No case-control enrichment data were identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Available evidence is insufficient to assign PM6 points. Details ▾Hide ▴
PP1 No segregation data were identified for this variant. Available evidence does not support PP1. Details ▾Hide ▴
Rule
Requires at least 3 informative meioses for supporting strength.
Evidence considered
- No family segregation evidence was identified.
Still missing
- No informative meioses were identified.
Sources
BS2 This variant is present in population databases, including one homozygote, but no confirmed unaffected clinical individuals meeting the RASopathy VCEP point-based BS2 framework were identified. Available evidence is insufficient to apply BS2. Details ▾Hide ▴
Rule
Point-based unaffected observations are required.
Evidence considered
- gnomAD v2.1 reports 1 homozygote.
- gnomAD v4.1 reports 1 homozygote.
Still missing
- No phenotype-confirmed unaffected individuals were identified.
- No BS2 point total was identified.
Sources
BS4 No segregation data showing lack of cosegregation were identified for this variant. Available evidence is insufficient to apply BS4. Details ▾Hide ▴
Rule
Requires informative nonsegregation evidence.
Evidence considered
- No family nonsegregation evidence was identified.
Still missing
- No informative meiosis showing nonsegregation was identified.
Sources
BP2 No evidence was identified showing this variant occurring with an alternative molecular explanation in the same gene that would support BP2 point assignment. Details ▾Hide ▴
Rule
Point-based alternative molecular explanation in the same gene.
Evidence considered
- No BP2-relevant case data were identified.
Still missing
- No phase or alternative-cause data in the same gene were identified.
Sources
BP5 No evidence was identified showing a different molecular explanation for the phenotype in another gene or a phenotype fully explained by another cause. Available evidence is insufficient to apply BP5. Details ▾Hide ▴
Rule
Point-based alternative molecular explanation in a different gene or phenotype explained by another cause.
Evidence considered
- No BP5-relevant alternative-cause evidence was identified.
Still missing
- No alternative molecular diagnosis was identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is an intronic +3 splice-region change, not a canonical ±1,2 splice-site variant, nonsense variant, or frameshift variant. The BRAF RASopathy VCEP marks PVS1 as not applicable here, and the generic PVS1 scaffold does not support applying PVS1 to this variant class. Details ▾Hide ▴
Rule
Not applicable for this VCEP/variant context.
Evidence considered
- Variant position is c.2127+3A>G.
- Generic PVS1 scaffold states this variant is outside default null-variant buckets.
Sources
PS1 N/APS1 applies to the same amino acid change as a previously established pathogenic variant. This variant is an intronic splice-region change with no defined amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Protein consequence is p.?.
- Variant is intronic rather than missense.
Sources
PM1 N/APM1 in this BRAF specification is limited to defined protein domains and hotspots. This variant is an intronic splice-region change without a defined amino acid residue in those domains, so PM1 is not applicable. Details ▾Hide ▴
Rule
Applicable only to specified functional domains and hotspots.
Evidence considered
- Variant consequence is intronic c.2127+3A>G with protein effect p.?.
Sources
PM3 N/APM3 is not applicable in this BRAF RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- RASopathy BRAF VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is intended for protein length changes from in-frame insertions/deletions or stop-loss variants. This variant is an intronic splice-region substitution and does not match that variant class. Details ▾Hide ▴
Rule
Protein length change criterion.
Evidence considered
- Variant is an intronic single-nucleotide substitution.
Sources
PM5 N/APM5 applies to a novel missense change at a residue where another pathogenic missense change has been established. This variant is not a missense change, so PM5 is not applicable. Details ▾Hide ▴
Rule
Novel missense change at a residue with another pathogenic missense change.
Evidence considered
- Protein consequence is p.?.
- Variant is intronic rather than missense.
Sources
PP2 N/APP2 applies to missense variants in genes with low benign missense variation. This variant is an intronic splice-region variant rather than a missense variant, so PP2 is not applicable. Details ▾Hide ▴
Rule
Missense-specific criterion.
Evidence considered
- Variant is intronic and does not encode a missense change.
Sources
PP4 N/APP4 is not applicable in this BRAF RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- RASopathy BRAF VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use.
Evidence considered
- VCEP specifies PP5 is not for use.
Sources
BS3 N/ABS3 is not applicable in this BRAF RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- RASopathy BRAF VCEP marks BS3 as not applicable.
Sources
BP1 N/AIn this VCEP, BP1 is used for truncating or loss-of-function variants in a gain-of-function disease setting when loss of function is not an established disease mechanism. This variant is a noncanonical intronic splice-region change without evidence of a truncating effect, so BP1 is not applicable. Details ▾Hide ▴
Rule
Used for truncating/LOF variants in the specified RASopathy context.
Evidence considered
- Variant is c.2127+3A>G.
- SpliceAI predicts no significant splice impact.
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- RASopathy BRAF VCEP marks BP3 as not applicable.
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.2127+3A>G
- Protein (HGVS p.)
- NP_001341538.1:p.?
- GRCh38
- chr7:140739809 T>C
- GRCh37
- chr7:140439609 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
152 / 1,612,098 alleles
AF 9.43e-05 · 1 homozygotes · FAF 0.00138
gnomAD v2.1
50 / 282,650 alleles
AF 0.000177 · 1 homozygotes · FAF 0.00159
By genetic ancestry
gnomAD v4.1
AF 9.4e-05 · 152 / 1,612,098 alleles · 1 hom · FAF 0.0014
| African/African American121 / 74,992 | 0.00161 hom |
| Middle Eastern1 / 4,552 | 0.00022 |
| Admixed American10 / 60,026 | 0.00017 |
| Remaining individuals9 / 62,340 | 0.00014 |
| European (non-Finnish)11 / 1,179,932 | 9.3e-06 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00018 · 50 / 282,650 alleles · 1 hom · FAF 0.0016
| African/African American43 / 24,968 | 0.00171 hom |
| Admixed American5 / 35,426 | 0.00014 |
| European (non-Finnish)2 / 129,056 | 1.5e-05 |
0 alternate alleles recorded in 5 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.42871e-05; MAF= 0.00943%, 152/1612098 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00161351; MAF= 0.16135%, 121/74992 alleles, homozygotes = 1); grpmax FAF= 0.00137943.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000176897; MAF= 0.01769%, 50/282650 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0017222; MAF= 0.17222%, 43/24968 alleles, homozygotes = 1); grpmax FAF= 0.0015909.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable computational evidence predicts little or no splice effect. SpliceAI shows a maximum delta score of 0.16, which does not support a meaningful abnormal splicing outcome, so the in silico evidence supports BP4 for a splice-region variant in this VCEP framework. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.00
- DS_AL 0.00
- DS_DG 0.16
- DS_DL 0.01.
- SpliceAI max delta score 0.16.
Sources
BP7 SupportingThis variant is a noncanonical intronic splice-region change at +3, and the BRAF RASopathy VCEP allows BP7 for intronic positions outside canonical splice sites when used with BP4. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.16, which supports BP7. Details ▾Hide ▴
Rule
Applicable for intronic positions except canonical splice sites and used in conjunction with BP4 when splicing impact is not predicted.
Evidence considered
- Variant position is +3 and therefore outside the canonical ±1
- 2 splice site.
- SpliceAI max delta score 0.16.
Sources
PP3 For splicing impact, PP3 requires computational evidence supporting an abnormal outcome consistent with disease mechanism. SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.16, so available in silico evidence does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_DG 0.16.
- SpliceAI max delta score 0.16.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16).
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
152 / 1,612,098 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 ↗
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/41447/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140439609-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140739809-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/BRAF/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.2127+3A%3EG
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= 9.42871e-05; MAF= 0.00943%, 152/1612098 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00161351; MAF= 0.16135%, 121/74992 alleles, homozygotes = 1); grpmax FAF= 0.00137943.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000176897; MAF= 0.01769%, 50/282650 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0017222; MAF= 0.17222%, 43/24968 alleles, homozygotes = 1); grpmax FAF= 0.0015909.
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).