Classification rationale

BA1BP4BP6 Benign

BRAF c.1383A>G

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 461.¹ 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%.² 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 0.084.³

BA1 + BP4 + BP6 → Benign

1 clinvar ↗hotspots ↗

2 gnomad_v2 ↗cspec ↗

3 spliceai ↗revel

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_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 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 · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

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%.

gnomAD v2.1 total AF 0.12339%.gnomAD v2.1 grpmax FAF 1.2192%.BA1 threshold is filtering AF ≥0.05%.

gnomad_v2 ↗cspec ↗

BP4 supporting Benign

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.

SpliceAI max delta score 0.01.REVEL score 0.084.BP4 threshold is REVEL ≤0.3 or negligible predicted splice effect.

spliceai ↗cspec ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

BRAF RASopathy VCEP marks BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 11 not assessed

Pathogenic

PS2 No confirmed de novo observation with parental testing and phenotype-based point scoring was identified for this variant.

PS3 No approved functional study for this exact variant was identified in the reviewed RASopathy VCEP functional materials.

PS4 No affected-individual enrichment or point-based case evidence was identified to support PS4 for this variant.

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.

PM2 This variant is present in gnomAD and therefore is not absent from controls, so PM2 is not met.

PM6 No presumed de novo observation without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Computational evidence does not support a damaging effect.

Benign

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.

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.

BS4 No non-segregation data were identified for this variant.

BP2 No phase data or alternative molecular explanation in the same gene were identified for this variant.

BP5 No alternative molecular diagnosis in another gene or fully explanatory non-RASopathy diagnosis was identified for this variant.

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.

N/A · 11 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.075% · 1206 / 1,614,110
12 hom · FAF 1.3%

African/African American 1007 / 75,040	1.3% 9 hom
Remaining individuals 62 / 62,508	0.099% 1 hom
Middle Eastern 6 / 6,062	0.099%
Admixed American 39 / 60,014	0.065% 1 hom
South Asian 13 / 91,084	0.014% 1 hom
European (non-Finnish) 79 / 1,180,000	0.0067%

+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.12% · 349 / 282,834
3 hom · FAF 1.2%

African/African American 325 / 24,972	1.3% 3 hom
Remaining individuals 2 / 7,228	0.028%
Admixed American 7 / 35,432	0.02%
South Asian 5 / 30,612	0.016%
European (non-Finnish) 10 / 129,156	0.0077%

+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.084.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104607983, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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