3-12663990-C-G
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002880.4(RAF1):c.-204G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 398,582 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0018 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0024 ( 2 hom. )
Consequence
RAF1
NM_002880.4 5_prime_UTR
NM_002880.4 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.43
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 -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.61).
BP6
?
Variant 3-12663990-C-G is Benign according to our data. Variant chr3-12663990-C-G is described in ClinVar as [Benign]. Clinvar id is 40576.Status of the report is reviewed_by_expert_panel, 3 stars.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00181 (276/152322) while in subpopulation NFE AF= 0.00316 (215/68006). AF 95% confidence interval is 0.00282. There are 2 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd at 276 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.-204G>C | 5_prime_UTR_variant | 1/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.-204G>C | 5_prime_UTR_variant | 1/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00181 AC: 276AN: 152204Hom.: 2 Cov.: 33
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GnomAD4 exome AF: 0.00238 AC: 586AN: 246260Hom.: 2 Cov.: 0 AF XY: 0.00254 AC XY: 317AN XY: 124834
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ClinVar
Significance: Benign
Submissions summary: Uncertain:2Benign:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | RAF1: BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
LEOPARD syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Noonan syndrome 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 25, 2011 | -204G>C in the 5'UTR of RAF1: This variant has been identified in our laboratory in four probands with clinical features of Noonan spectrum disorders. However, this variant was also identified in a parent of three of these individuals who r eportedly do not have clinical features associated with Noonan spectrum disorder s. Furthermore, this variant is located in the 5'UTR and although variants in re gulatory regions could have an effect on transcriptional or translational effici ency, variants of this type have not been reported in Noonan spectrum disorders to date. Therefore, this variant is likely to be benign. - |
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 11, 2021 | - - |
RASopathy Benign:1
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Nov 04, 2019 | The c.-204G>C variant in RAF1 is classified as benign because it has been identified in 0.15126% (95% CI of 32/15402) of non-Finnish European chromosomes 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). ACMG/AMP Criteria applied: BA1, BP4, BP7. - |
Computational scores
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
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