Classification rationale

BP4BP6BS1BA1 Benign

BRAF c.1929A>G

The BRAF c.1929A>G (p.Gly643=) variant is reported in ClinVar as Benign with expert-panel review.¹ This variant is common in population databases, with an allele frequency of 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1, far above the RASopathy VCEP BA1 threshold of 0.05% and BS1 threshold of 0.025%.² Computational evidence does not support a damaging effect, with a REVEL score of 0.247 and SpliceAI predicting no significant splice impact with a maximum delta score of 0.01.³

BP4 + BP6 + BS1 + BA1 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelspliceai ↗cspec ↗

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 · 4 applied · 13 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant exceeds the RASopathy VCEP BA1 threshold by a large margin. The filtering allele frequency threshold is 0.05%, while the observed allele frequency is 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1; both values are far above the stand-alone benign threshold.

gnomAD v2.1 AF 0.211808gnomAD v4.1 AF 0.178251

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 strong Benign

This variant exceeds the RASopathy VCEP BS1 population threshold. The filtering allele frequency threshold is 0.025%, whereas the observed allele frequency is 21.18080% in gnomAD v2.1 and 17.82506% in gnomAD v4.1, with many homozygotes in both datasets.

gnomAD v2.1 AF 0.211808 with 10008 homozygotesgnomAD v4.1 AF 0.178251 with 37

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting Benign

Computational evidence supports no meaningful molecular effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, and the REVEL score is 0.247, which is below the RASopathy VCEP benign threshold of 0.3.

SpliceAI max delta score 0.01REVEL score 0.247

cspec ↗spliceai ↗

BP6 supporting Benign

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

Criterion designated not applicable by the VCEPClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 cannot be assigned from the available evidence.

PS3 No approved functional study for this exact variant was identified in the available RASopathy VCEP functional materials, so PS3 cannot be assigned.

PS4 Available evidence does not support enrichment in affected individuals.

PM1 Available evidence does not support PM1.

PM2 PM2 requires absence from gnomAD, but this variant is common in population databases.

PM6 No assumed de novo occurrence without parental confirmation was identified for this variant, so PM6 cannot be assigned from the available evidence.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed from the available evidence.

PP3 Computational evidence does not support a deleterious effect.

Benign

BS2 The available materials show this variant is very common in population databases, including many homozygotes, but no explicit BS2 point-based healthy-individual assessment under the RASopathy framework was provided.

BS4 No informative family showing lack of segregation was identified for this variant, so BS4 cannot be assigned from the available evidence.

BP2 No phase data or evidence for an alternative molecular explanation in the same gene were identified, so BP2 cannot be assessed from the available information.

BP5 No evidence was identified for an alternative molecular explanation in a different gene or for a phenotype fully explained by another cause, so BP5 cannot be assessed from the available information.

BP7 This synonymous variant has no predicted splice effect by SpliceAI, which supports one part of BP7, but no conservation evidence was identified to show 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= 0.178251; MAF= 17.82506%, 287439/1612556 alleles, homozygotes = 37917) and has highest observed frequency in the African/African American population (AF= 0.676837; MAF= 67.68368%, 50668/74860 alleles, homozygotes = 17235); grpmax FAF= 0.671898.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.211808; MAF= 21.18080%, 59743/282062 alleles, homozygotes = 10008) and has highest observed frequency in the African/African American population (AF= 0.678583; MAF= 67.85829%, 16894/24896 alleles, homozygotes = 5737); grpmax FAF= 0.669859.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

18% · 287439 / 1,612,556
37917 hom · FAF 67%

African/African American 50668 / 74,860	68% 17235 hom
Middle Eastern 1836 / 5,786	32% 330 hom
South Asian 28659 / 91,040	31% 4759 hom
Ashkenazi Jewish 6216 / 29,556	21% 680 hom
Remaining individuals 12595 / 62,418	20% 1501 hom
East Asian 7086 / 44,748	16% 620 hom
European (Finnish) 9213 / 63,930	14% 687 hom
European (non-Finnish) 163217 / 1,179,344	14% 11485 hom
Admixed American 7854 / 59,962	13% 618 hom
Amish 95 / 912	10% 2 hom

gnomAD v2.1

21% · 59743 / 282,062
10008 hom · FAF 67%

African/African American 16894 / 24,896	68% 5737 hom
South Asian 9619 / 30,588	31% 1619 hom
Ashkenazi Jewish 2175 / 10,362	21% 231 hom
East Asian 3750 / 19,946	19% 370 hom
Remaining individuals 1318 / 7,198	18% 154 hom
European (Finnish) 3751 / 25,082	15% 292 hom
European (non-Finnish) 18559 / 128,644	14% 1418 hom
Admixed American 3677 / 35,346	10% 187 hom

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40391)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.247.

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; COSV56058907, n = 37 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

Triaged references · 6 PMIDs not cited in assessment

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

20301303 ↗ Noonan Syndrome. CLINVAR

20301557 ↗ Noonan Syndrome with Multiple Lentigines. CLINVAR

20876176 ↗ Noonan syndrome: clinical features, diagnosis, and management guidelines. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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