rs397516898
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_001374258.1(BRAF):c.2248-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 80,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000012 ( 0 hom., cov: 28)
Exomes 𝑓: 8.0e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
BRAF
NM_001374258.1 splice_polypyrimidine_tract, intron
NM_001374258.1 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.0004428
2
Clinical Significance
Conservation
PhyloP100: 0.161
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 -10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
Variant 7-140734780-A-G is Benign according to our data. Variant chr7-140734780-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 44819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.2248-10T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000644969.2 | |||
BRAF | NM_004333.6 | c.2128-10T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.2248-10T>C | splice_polypyrimidine_tract_variant, intron_variant | NM_001374258.1 | |||||
BRAF | ENST00000646891.2 | c.2128-10T>C | splice_polypyrimidine_tract_variant, intron_variant | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000124 AC: 1AN: 80550Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.0000117 AC: 2AN: 170526Hom.: 0 AF XY: 0.0000105 AC XY: 1AN XY: 95678
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.97e-7 AC: 1AN: 1254556Hom.: 0 Cov.: 29 AF XY: 0.00000161 AC XY: 1AN XY: 622346
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GnomAD4 genome ? AF: 0.0000124 AC: 1AN: 80592Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 37578
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 09, 2012 | 2128-10T>C in intron 17 of BRAF: This variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Although positions -3 an d -5 to -12 are part of the splicing consensus sequence and variants involving t hese positions sometimes affect splicing, pathogenic splicing variants have not been reported in Noonan spectrum disorders. Therefore, this variant is likely to be benign. - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
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Name
Calibrated prediction
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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