rs397507454
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.36G>A (p.Ala12=) variant in the BRAF gene is 0.116% (14/7290) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA281921/MONDO:0021060/004
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 4 hom. )
Consequence
BRAF
NM_004333.6 synonymous
NM_004333.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0780
Genes affected
BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRAF | NM_001374258.1 | c.36G>A | p.Ala12Ala | synonymous_variant | 1/20 | ENST00000644969.2 | NP_001361187.1 | |
| BRAF | NM_004333.6 | c.36G>A | p.Ala12Ala | synonymous_variant | 1/18 | ENST00000646891.2 | NP_004324.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRAF | ENST00000644969.2 | c.36G>A | p.Ala12Ala | synonymous_variant | 1/20 | NM_001374258.1 | ENSP00000496776.1 | |||
| BRAF | ENST00000646891.2 | c.36G>A | p.Ala12Ala | synonymous_variant | 1/18 | NM_004333.6 | ENSP00000493543.1 |
Frequencies
GnomAD3 genomes 0.000172 AC: 26AN: 150876Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000726 AC: 78AN: 107470Hom.: 0 AF XY: 0.00102 AC XY: 61AN XY: 59850
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GnomAD4 exome AF: 0.000335 AC: 383AN: 1144176Hom.: 4 Cov.: 16 AF XY: 0.000444 AC XY: 255AN XY: 574280
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GnomAD4 genome 0.000172 AC: 26AN: 150986Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 14AN XY: 73766
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ClinVar
Significance: Benign
Submissions summary: Benign:10
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:3
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | BRAF: BP4, BP7 - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2017 | Variant summary: The BRAF c.36G>A (p.Ala12Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 83/134502 control chromosomes in genomAD at a frequency of 0.0006171, which is approximately 247 times the estimated maximal expected allele frequency of a pathogenic BRAF variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. - |
RASopathy Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2023 | - - |
| Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.36G>A (p.Ala12=) variant in the BRAF gene is 0.116% (14/7290) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) - |
Noonan syndrome 7 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
BRAF-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 17, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
LEOPARD syndrome 3 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome and Noonan-related syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at