rs727504451
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_002880.4(RAF1):c.1108+9_1108+21del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00065 in 1,592,256 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 2 hom. )
Consequence
RAF1
NM_002880.4 intron
NM_002880.4 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.84
Genes affected
RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 3-12599669-AAAGGGAGGGCCCC-A is Benign according to our data. Variant chr3-12599669-AAAGGGAGGGCCCC-A is described in ClinVar as [Benign]. Clinvar id is 178666.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-12599669-AAAGGGAGGGCCCC-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000394 (60/152148) while in subpopulation NFE AF= 0.00072 (49/68026). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd at 60 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.1108+9_1108+21del | intron_variant | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.1108+9_1108+21del | intron_variant | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000394 AC: 60AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000358 AC: 90AN: 251410Hom.: 0 AF XY: 0.000346 AC XY: 47AN XY: 135888
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GnomAD4 exome AF: 0.000677 AC: 975AN: 1440108Hom.: 2 AF XY: 0.000623 AC XY: 447AN XY: 717922
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
RASopathy Benign:3
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.1108+9_1108+21del variant in the RAF1 gene has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR Lab ID's: 26957, 21766; ClinVar SCV000205113.4, SCV000209007.2). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The filtering allele frequency of the c.1108+9_1108+21del variant in the RAF1 gene is 0.0637% (54/66698) for European (Non-Finnish) 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 for autosomal dominant RASopathy variants (BA1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5, BP7. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2014 | The variant is found in NOONAN panel(s). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 31, 2015 | c.1108+9_1108+21del in intron 10 of RAF1: This variant is not expected to have c linical significance because it does not alter an amino acid residue, is not loc ated within the splice consensus sequence, and splice prediction models do not s uggest an impact to splicing. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 05, 2021 | Variant summary: RAF1 c.1108+9_1108+21del13 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00036 in 251410 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome And Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign, including a benign classification by ClinGen RASopathy Variant Curation Expert Panel. Based on the evidence outlined above, the variant was classified as benign. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | May 01, 2018 | - - |
Noonan syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 22, 2020 | The c.1168+9_1168+21del splice region variant has a frequency of 0.0003465 (98 of 282,788 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0006814 (88 of 129,138) in the European non-Finnish population (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1). This variant is not predicted to impact splicing (BP7). This variant has been classified as benign by the ClinGen RASopathy Variant Curation Expert Panel with additional unpublished patient data (SCV000616427.3). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BA1, BP7. - |
RAF1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 08, 2019 | 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). - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at