rs766063111
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2
The NM_006912.6(RIT1):c.644_647del(p.Lys215IlefsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0001 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000094 ( 0 hom. )
Consequence
RIT1
NM_006912.6 frameshift
NM_006912.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.52
Genes affected
RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0242 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
BP6
?
Variant 1-155900400-ATCTT-A is Benign according to our data. Variant chr1-155900400-ATCTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 506383.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152300) while in subpopulation AMR AF= 0.000524 (8/15274). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 25 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RIT1 | NM_006912.6 | c.644_647del | p.Lys215IlefsTer3 | frameshift_variant | 6/6 | ENST00000368323.8 | |
RIT1 | NM_001256820.2 | c.536_539del | p.Lys179IlefsTer3 | frameshift_variant | 5/5 | ||
RIT1 | NM_001256821.2 | c.695_698del | p.Lys232IlefsTer3 | frameshift_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RIT1 | ENST00000368323.8 | c.644_647del | p.Lys215IlefsTer3 | frameshift_variant | 6/6 | 1 | NM_006912.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251364Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135848
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GnomAD4 exome AF: 0.0000938 AC: 137AN: 1461120Hom.: 0 AF XY: 0.0000935 AC XY: 68AN XY: 726918
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Noonan syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Lys215Ilefs*3) in the RIT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the RIT1 protein. This variant is present in population databases (rs766063111, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 506383). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | Variant summary: RIT1 c.644_647delAAGA (p.Lys215IlefsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however the molecular mechanism of disease attributed to RIT1 is gain-of-function. The variant allele was found at a frequency of 9.2e-05 in 251364 control chromosomes, predominantly at a frequency of 0.00035 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in RIT1 causing Noonan Syndrome phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.644_647delAAGA in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 506383). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | See Variant Classification Assertion Criteria. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2019 | This alteration is classified as likely 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
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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