rs374061873
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_002524.5(NRAS):c.553C>T(p.Pro185Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. P185L) has been classified as Uncertain significance.
Frequency
Consequence
NM_002524.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRAS | NM_002524.5 | c.553C>T | p.Pro185Ser | missense_variant | 5/7 | ENST00000369535.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRAS | ENST00000369535.5 | c.553C>T | p.Pro185Ser | missense_variant | 5/7 | 1 | NM_002524.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251444Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135898
GnomAD4 exome AF: 0.0000801 AC: 117AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 727062
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74310
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2021 | Variant summary: NRAS c.553C>T (p.Pro185Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251444 control chromosomes. The observed variant frequency is approximately 27.044 fold of the estimated maximal expected allele frequency for a pathogenic variant in NRAS causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.553C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2014 | Pro185Ser in exon 5 of NRAS: This variant has not been previously reported in in dividuals with clinical features of Noonan syndrome, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu; dbSNP rs374061873). In addition, this variant was not identified in an unaffected father (LMM unpublished data). Pro185 is not well co nserved across species and the change to Serine (ser) has been seen in multiple mammals (shrew, opossum, and Tasmanian devil) and in many other more evolutionar ily distant species, suggesting that this change might be tolerated. Other compu tational prediction tools suggest that this variant may not impact the protein. In summary, the Pro185Ser variant is classified as likely benign based on its la ck of conservation and presence in an unaffected parent. - |
NRAS-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 11, 2023 | The NRAS c.553C>T variant is predicted to result in the amino acid substitution p.Pro185Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-115251173-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Noonan syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 185 of the NRAS protein (p.Pro185Ser). This variant is present in population databases (rs374061873, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 179025). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NRAS protein function with a negative predictive value of 95%. 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. - |
Noonan syndrome Benign:1
Likely benign, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at