chr3-12585118-T-C
Variant summary
Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1668+4A>G variant in the RAF1 gene is 0.053% (11/11576) of Latino 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/CA2259454/MONDO:0021060/004
Frequency
Consequence
NM_002880.4 splice_region, intron
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000147 AC: 37AN: 251274 AF XY: 0.000140 show subpopulations
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22AN XY: 727248 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
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RASopathy Benign:2
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The filtering allele frequency of the c.1668+4A>G variant in the RAF1 gene is 0.053% (11/11576) of Latino 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) -
not specified Benign:1
Variant summary: RAF1 c.1668+4A>G 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. Several computational tools predict an impact on normal splicing: Five predict the no significant impact on splicing. Four predict the variant strengthens a cryptic intronic 5' donor site. However, these predictions have yet to be confirmed by functional studies The variant allele was found at a frequency of 0.00013 in 276966 control chromosomes (gnomAD), reported exclusively within the Latino subpopulation at a frequency of 0.0011 in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 44 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 Latino origin. To our knowledge, no occurrence of c.1668+4A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2 calling it VUS, and one classifying it as likely benign, and the ClinGen expert panel has classified it as Benign). Based on the evidence outlined above, the variant was classified as benign. -
Cardiovascular phenotype Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at