1-155900400-ATCTT-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2
The NM_006912.6(RIT1):c.644_647delAAGA(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
Consequence
NM_006912.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RIT1 | NM_006912.6 | c.644_647delAAGA | p.Lys215IlefsTer3 | frameshift_variant | Exon 6 of 6 | ENST00000368323.8 | NP_008843.1 | |
RIT1 | NM_001256821.2 | c.695_698delAAGA | p.Lys232IlefsTer3 | frameshift_variant | Exon 6 of 6 | NP_001243750.1 | ||
RIT1 | NM_001256820.2 | c.536_539delAAGA | p.Lys179IlefsTer3 | frameshift_variant | Exon 5 of 5 | NP_001243749.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251364Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135848
GnomAD4 exome AF: 0.0000938 AC: 137AN: 1461120Hom.: 0 AF XY: 0.0000935 AC XY: 68AN XY: 726918
GnomAD4 genome AF: 0.000164 AC: 25AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74472
ClinVar
Submissions by phenotype
Noonan syndrome 8 Uncertain:2
The RIT1 c.644_647del; p.Lys215IlefsTer3 variant (rs766063111), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 506383). This variant is found in the general population with an overall allele frequency of 0.0001% (31/282,772 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the RIT1 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. However, the functional consequences of this truncation are unclear in the context of RIT1-associated disease, which is primarily associated with missense variants (Zha 2022). Due to limited information, the clinical significance of the c.644_647del variant is uncertain at this time. References: Zha P et al. Noonan syndrome caused by RIT1 gene mutation: A case report and literature review. Front Pediatr. 2022 Sep 7;10:934808. PMID: 36160792 -
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
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
See Variant Classification Assertion Criteria. -
Cardiovascular phenotype Benign:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at