chr3-12585161-C-G
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1629G>C (p.Thr543=) variant in the RAF1 gene is 0.054% (9/8654) of East Asian 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 (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA235376/MONDO:0021060/004
Frequency
Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00040 ( 12 hom. )
Consequence
RAF1
NM_002880.4 synonymous
NM_002880.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.54
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]
MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BA1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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RAF1 | NM_002880.4 | c.1629G>C | p.Thr543= | synonymous_variant | 15/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.1629G>C | p.Thr543= | synonymous_variant | 15/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000835 AC: 21AN: 251378Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135858
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GnomAD4 exome AF: 0.000400 AC: 585AN: 1461888Hom.: 12 Cov.: 33 AF XY: 0.000377 AC XY: 274AN XY: 727246
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GnomAD4 genome AF: 0.000230 AC: 35AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74464
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:10
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2016 | Variant summary: The RAF1 c.1629G>C (p.Thr543Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant, but 5/5 splicing algorithms predict no significant change to splicing. This variant was found in 11/121396 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.00104 (9/8654). This subpopulation frequency is about 42 times the estimated maximal expected allele frequency of a pathogenic RAF1 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been observed in one Japanese Kabuki Syndrome patient (Kuniba_ AJMG_2008) and one South Indian individual phenotype not specified (Dhandapany_Nat Genet_2015); data was not provided to suggest a causal relationship with the variant of interest. Additionally, one clinical diagnostic laboratory classified this variant as a VUS without providing evidence to independently evaluate. Taken together, this variant is classified as Benign based on the nature of the variant and the high allele frequency in the East Asian ExAC subpopulation. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 03, 2023 | - - |
RASopathy Benign:2
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.1629G>C (p.Thr543=) variant in the RAF1 gene is 0.054% (9/8654) of East Asian 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 (BA1; PMID:29493581) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
LEOPARD syndrome 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
RAF1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 02, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Computational scores
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Name
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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