rs373359206
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_006270.5(RRAS):c.49G>T(p.Gly17Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000374 in 1,497,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17V) has been classified as Uncertain significance.
Frequency
Consequence
NM_006270.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RRAS | NM_006270.5 | c.49G>T | p.Gly17Trp | missense_variant | 1/6 | ENST00000246792.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RRAS | ENST00000246792.4 | c.49G>T | p.Gly17Trp | missense_variant | 1/6 | 1 | NM_006270.5 | P1 | |
RRAS | ENST00000601532.1 | n.73G>T | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 151990Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000543 AC: 5AN: 92070Hom.: 0 AF XY: 0.0000188 AC XY: 1AN XY: 53140
GnomAD4 exome AF: 0.0000141 AC: 19AN: 1345656Hom.: 0 Cov.: 31 AF XY: 0.0000120 AC XY: 8AN XY: 664874
GnomAD4 genome ? AF: 0.000243 AC: 37AN: 151990Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74240
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 09, 2022 | Variant summary: RRAS c.49G>T (p.Gly17Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 92070 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.49G>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2022 | 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. - |
Noonan syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 18, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 575657). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. This variant is present in population databases (rs373359206, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 17 of the RRAS protein (p.Gly17Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at