7-140739809-T-C
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2
The NM_001374258.1(BRAF):c.2247+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000943 in 1,612,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
BRAF
NM_001374258.1 splice_donor_region, intron
NM_001374258.1 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.01395
2
Clinical Significance
Conservation
PhyloP100: 0.369
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 -18 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
?
Variant 7-140739809-T-C is Benign according to our data. Variant chr7-140739809-T-C is described in ClinVar as [Benign]. Clinvar id is 41447.Status of the report is reviewed_by_expert_panel, 3 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000427 (65/152320) while in subpopulation AFR AF= 0.00144 (60/41572). AF 95% confidence interval is 0.00115. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 65 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.2247+3A>G | splice_donor_region_variant, intron_variant | ENST00000644969.2 | |||
BRAF | NM_004333.6 | c.2127+3A>G | splice_donor_region_variant, intron_variant | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.2247+3A>G | splice_donor_region_variant, intron_variant | NM_001374258.1 | |||||
BRAF | ENST00000646891.2 | c.2127+3A>G | splice_donor_region_variant, intron_variant | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000427 AC: 65AN: 152202Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251252Hom.: 1 AF XY: 0.000162 AC XY: 22AN XY: 135786
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GnomAD4 exome AF: 0.0000596 AC: 87AN: 1459778Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34AN XY: 726178
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 31, 2015 | - - |
RASopathy Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.2127+3A>G variant in the BRAF gene is 0.151% (23/10398) of African 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) - |
Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2022 | - - |
Noonan syndrome 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
BRAF-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 05, 2022 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 29, 2016 | - - |
LEOPARD syndrome 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at