Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_002524.4 | Alternative | 4454 nt | 255–824 |
| NM_002524.5 | MANE Select | 4326 nt | 132–701 |
| NM_002524.3 | Alternative | 4461 nt | 255–824 |
| NM_002524.2 | Alternative | 1963 nt | 254–823 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 53 bp |
| Donor Loss (DL) | 0.0 | -117 bp |
| Acceptor Gain (AG) | 0.01 | 0 bp |
| Donor Gain (DG) | 0.0 | 271 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single‐exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows it is a missense change (A59D), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, applicable in RASopathy genes including NRAS." The evidence for this variant shows A59D is not identical to any previously established pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no evidence of confirmed de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires functional studies demonstrating a damaging effect. No functional assay data are available for NRAS A59D. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 is: "Strong: ≥5 probands with variant; Moderate: ≥3 points; Supporting: ≥1 point from case–control data." There are no case‐control or case series data. Therefore, this criterion is not applied.
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 is: "Moderate: Applicable only to critical and well‐established functional domains (SW2 [AA 57–64] for RASopathy genes)." The evidence for this variant shows A59D lies within the SW2 domain (AA 57–64) of NRAS. Therefore, this criterion is applied at Moderate strength.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: The variant must be absent from controls (gnomAD)." The evidence for this variant shows it is not present in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." NRAS‐related RASopathies are autosomal dominant, and there is no evidence of trans configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame deletions/insertions or stop‐loss variants." This variant is a missense change, not an in‐frame indel. Therefore, this criterion is not applied.
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate: One likely pathogenic residue change at the same codon (analogous gene)." The evidence for this variant shows that other missense changes at codon 59 (e.g., A59G) have been classified as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to VCEP guidelines, PM6 is a lower‐strength de novo criterion without confirmed maternity/paternity. No such evidence exists. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires segregation evidence in affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." NRAS RASopathies are gain‐of‐function; the gene has many pathogenic missense variants but also some benign ones. No specific PP2 rationale applies. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 is: "Supporting for missense, REVEL ≥0.7 or splicing predictions matching mechanism." REVEL score is unavailable and in silico predictors are mixed/benign. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires a highly specific phenotype matching a single gene. No clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory." ClinVar includes a single laboratory entry classifying A59D as Likely Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, BA1 is: "Stand Alone: GnomAD allele frequency ≥0.05%." The variant is absent (0%), well below the threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 is: "Strong: GnomAD filtering allele frequency ≥0.025%." The variant frequency is 0%, below the threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 requires observation in healthy adults inconsistent with disease penetrance. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires well‐validated functional studies showing no damaging effect. No functional data exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 requires lack of segregation or non‐segregation in affected members. No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to VCEP guidelines, BP1 applies to truncating variants in genes without established loss‐of‐function disease mechanism. This is a missense variant in NRAS, a gain‐of‐function disease mechanism. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 requires observation in trans or cis with a pathogenic variant for a recessive gene. NRAS RASopathies are dominant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in‐frame deletions/insertions in repetitive regions. This variant is missense and not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." In silico tools (CADD score 5.57, SpliceAI 0.01) predict benign effect. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular cause. No such alternate cause is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 is: "Reputable source reports variant as benign without available evidence." No such benign classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous or noncoding variants with no splice impact. This is a missense variant. Therefore, this criterion is not applied.