rs527774250
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The ENST00000688543.1(RAF1):c.-337_-336del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 396,792 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0037 ( 2 hom. )
Consequence
RAF1
ENST00000688543.1 5_prime_UTR
ENST00000688543.1 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.61
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 3-12664121-ACT-A is Benign according to our data. Variant chr3-12664121-ACT-A is described in ClinVar as [Benign]. Clinvar id is 40573.Status of the report is reviewed_by_expert_panel, 3 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00305 (460/150778) while in subpopulation NFE AF= 0.00537 (363/67616). AF 95% confidence interval is 0.00491. There are 0 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 460 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | upstream_gene_variant | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | upstream_gene_variant | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00305 AC: 460AN: 150660Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00373 AC: 917AN: 246014Hom.: 2 AF XY: 0.00364 AC XY: 454AN XY: 124706
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GnomAD4 genome ? AF: 0.00305 AC: 460AN: 150778Hom.: 0 Cov.: 32 AF XY: 0.00284 AC XY: 209AN XY: 73604
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ClinVar
Significance: Benign
Submissions summary: Uncertain:2Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Noonan syndrome with multiple lentigines Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Noonan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2011 | -337_-336delAG in 5'UTR of exon 1 of RAF1: This variant has been identified in o ur laboratory in one individual who is reportedly unaffected with the clinical f eatures of the Noonan spectrum as well as five other probands with Noonan spectr um features who have a pathogenic PTPN11 variant. This variant occurs in the non -coding first exon of the gene. No variants in this region of RAF1 have been sho wn to be pathogenic to date. Therefore, this variant is not expected to have cli nical or pathological significance. - |
LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
RASopathy Benign:1
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Nov 04, 2019 | The c.-339_-338delAG variant in RAF1 is classified as benign because it has been identified in 0.33579% (95% CI of 63/15050) of non-Finnish European alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). This variant was identified in 4 individuals with Noonan syndrome who carried additional pathogenic variants in PTPN11 sufficient to explain their clinical presentations (BP5). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7. - |
Computational scores
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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