rs760978291
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_006270.5(RRAS):c.472_473insTT(p.Ser158PhefsTer77) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,583,240 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 0.00022 ( 0 hom., cov: 28)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
RRAS
NM_006270.5 frameshift
NM_006270.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.600
Genes affected
RRAS (HGNC:10447): (RAS related) The protein encoded by this gene is a small GTPase involved in diverse processes including angiogenesis, vascular homeostasis and regeneration, cell adhesion, and neuronal axon guidance. Mutations in this gene are found in many invasive cancers. [provided by RefSeq, Jul 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 19-49635833-G-GAA is Benign according to our data. Variant chr19-49635833-G-GAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582390.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RRAS | NM_006270.5 | c.472_473insTT | p.Ser158PhefsTer77 | frameshift_variant | 5/6 | ENST00000246792.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RRAS | ENST00000246792.4 | c.472_473insTT | p.Ser158PhefsTer77 | frameshift_variant | 5/6 | 1 | NM_006270.5 | P1 | |
| RRAS | ENST00000601532.1 | n.612_613insTT | non_coding_transcript_exon_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes 0.000224 AC: 34AN: 151622Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.000199 AC: 48AN: 241452Hom.: 0 AF XY: 0.000213 AC XY: 28AN XY: 131604
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GnomAD4 exome AF: 0.000287 AC: 411AN: 1431500Hom.: 0 Cov.: 29 AF XY: 0.000284 AC XY: 202AN XY: 710198
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GnomAD4 genome 0.000224 AC: 34AN: 151740Hom.: 0 Cov.: 28 AF XY: 0.000175 AC XY: 13AN XY: 74172
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Noonan syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Ser158Phefs*77) in the RRAS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the RRAS protein. This variant is present in population databases (rs760978291, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Noonan (Invitae). ClinVar contains an entry for this variant (Variation ID: 582390). 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 | Nov 09, 2020 | Variant summary: RRAS c.472_473insTT (p.Ser158PhefsX77) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0002 in 241452 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 168 fold of the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.472_473insTT in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at