NM_002880.4:c.321-14dupT
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1
The NM_002880.4(RAF1):c.321-14dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,550,984 control chromosomes in the GnomAD database, including 112 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_002880.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00391 AC: 594AN: 151892Hom.: 16 Cov.: 32
GnomAD3 exomes AF: 0.00939 AC: 2350AN: 250296Hom.: 78 AF XY: 0.00798 AC XY: 1081AN XY: 135416
GnomAD4 exome AF: 0.00278 AC: 3888AN: 1398974Hom.: 96 Cov.: 25 AF XY: 0.00260 AC XY: 1818AN XY: 699424
GnomAD4 genome AF: 0.00388 AC: 590AN: 152010Hom.: 16 Cov.: 32 AF XY: 0.00420 AC XY: 312AN XY: 74300
ClinVar
Submissions by phenotype
not specified Benign:3
c.321-14_321-13insT in intron 3 of RAF1: This variant is not expected to have cl inical significance because it has been identified in 6.7% (573/8544) of East As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs202103447). -
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Variant summary: RAF1 c.321-14dupT 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. 5/5 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 0.0088 in 281456 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 350 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 benign. To our knowledge, no occurrence of c.321-14dupT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign and 1x likely benign). Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
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. -
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Noonan syndrome with multiple lentigines Benign:1
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Noonan syndrome Benign:1
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RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at