rs2230917
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_006270.5(RRAS):āc.568G>Cā(p.Val190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000219 in 1,570,188 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).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RRAS | NM_006270.5 | c.568G>C | p.Val190Leu | missense_variant | Exon 5 of 6 | ENST00000246792.4 | NP_006261.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00122 AC: 185AN: 152112Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000308 AC: 75AN: 243620Hom.: 0 AF XY: 0.000182 AC XY: 24AN XY: 131936
GnomAD4 exome AF: 0.000112 AC: 159AN: 1417958Hom.: 0 Cov.: 31 AF XY: 0.0000871 AC XY: 61AN XY: 700596
GnomAD4 genome AF: 0.00122 AC: 185AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.00102 AC XY: 76AN XY: 74436
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
The p.V190L variant (also known as c.568G>C), located in coding exon 5 of the RRAS gene, results from a G to C substitution at nucleotide position 568. The valine at codon 190 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Variant summary: RRAS c.568G>C (p.Val190Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 274984 control chromosomes, predominantly at a frequency of 0.0045 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1800 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 African or African-American origin. To our knowledge, no occurrence of c.568G>C 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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided Benign:1
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Noonan syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at