rs3730270
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002880.4(RAF1):c.321-14T>A 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 0.00059 in 1,541,572 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00056 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00059 ( 8 hom. )
Consequence
RAF1
NM_002880.4 splice_polypyrimidine_tract, intron
NM_002880.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.987
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=-0.83).
BP6
?
Variant 3-12609349-A-T is Benign according to our data. Variant chr3-12609349-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 178110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-12609349-A-T is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000556 (84/151104) while in subpopulation EAS AF= 0.0147 (66/4484). AF 95% confidence interval is 0.0119. There are 2 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 84 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.321-14T>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.321-14T>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000556 AC: 84AN: 150978Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00108 AC: 266AN: 245888Hom.: 1 AF XY: 0.000960 AC XY: 128AN XY: 133376
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GnomAD4 exome AF: 0.000594 AC: 826AN: 1390468Hom.: 8 Cov.: 25 AF XY: 0.000578 AC XY: 402AN XY: 695758
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GnomAD4 genome ? AF: 0.000556 AC: 84AN: 151104Hom.: 2 Cov.: 32 AF XY: 0.000528 AC XY: 39AN XY: 73832
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 12, 2015 | c.321-14T>A in intron 3 of RAF1: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 1.7% (129/7460) of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs3730270). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 01, 2020 | Variant summary: RAF1 c.321-14T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 3/4 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 0.001 in 276986 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 600 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.321-14T>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 26, 2017 | 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. - |
LEOPARD syndrome 2 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. - |
Noonan syndrome 5 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. - |
RASopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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