NRAS c.157T>C, p.Leu53=
NM_002524.4:c.157T>C
Likely Benign
The variant is absent from population databases (PM2_supporting), computational analyses predict no functional or splicing impact (BP4_supporting), and reputable sources report it as benign (BP6_supporting). Combined supporting benign evidence yields a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
Genetic Information
Gene & Transcript Details
Gene
NRAS
Transcript
NM_002524.5
MANE Select
Total Exons
7
Strand
Reverse (−)
Reference Sequence
NC_000001.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_002524.3 | Alternative | 7 exons | Reverse |
| NM_002524.2 | Alternative | 7 exons | Reverse |
| NM_002524.4 | Alternative | 7 exons | Reverse |
Variant Details
HGVS Notation
NM_002524.4:c.157T>C
Protein Change
L53=
Location
Exon 3
(Exon 3 of 7)
5'Exon Structure (7 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_002524.5
Genome Browser
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HGVS InputNM_002524:c.157T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single 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 synonymous (silent) change with no predicted impact on splicing. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
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 for observed analogous pathogenic residue positions in HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.' The evidence for this variant shows: it results in no amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong 4 Points; Strong 2 Points; Moderate 1 Point for de novo occurrence.' The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Moderate Two or more different approved assays; Supporting One approved assay for functional studies.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong ≥5 points; Moderate ≥3 points; Supporting ≥1 point based on case-control or case-series data.' The evidence for this variant shows: no case-control or case-series data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Applicable only to critical and well-established functional domains (P-loop AA 10-17, SW1 AA 25-40, SW2 AA 57-64, SAK AA 145-156).' The evidence for this variant shows: it is a synonymous change outside these domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
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 absent from population databases including gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is not observed in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no data on zygosity or trans configuration. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes (in-frame indels or stop-loss) not in repetitive regions.' The evidence for this variant shows: it is a synonymous change with no protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Strong ≥2 different [likely] pathogenic residue changes at the same codon; Moderate 1 [likely] pathogenic residue change at the same codon.' The evidence for this variant shows: it is a synonymous change with no codon amino acid alteration. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Strong 2 Points; Moderate 1 Point; Supporting 0.5 Points for assumed de novo.' The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Strong ≥7 informative meioses; Moderate ≥5; Supporting ≥3 based on segregation.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting for missense variants in a gene with low rate of benign missense variation.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting for missense variants with REVEL ≥0.7 or splicing predictions matching mechanism.' The evidence for this variant shows: it is synonymous and SpliceAI predicts no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting when patient's phenotype is highly specific for a single gene disorder.' The evidence for this variant shows: no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting from a reputable source with pathogenic assertion without available evidence.' The evidence for this variant shows: no pathogenic assertions. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Stand Alone: Allele frequency ≥5% in population databases.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Strong: Allele frequency ≥2.5% in population databases.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Strong or Supporting based on observation in healthy individuals.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Strong: Well-established functional studies show no damaging effect on protein function.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Supporting for truncating variants in genes where loss of function is not a mechanism.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Strong/Moderate/Supporting for observed in cis/trans with pathogenic variant without contributing to disease.' The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame deletions/insertions in repetitive regions without known function.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Supporting: Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: SpliceAI predicts no splicing impact (max score 0.01) and other in silico tools show no deleterious effects. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting: Reputable source reports variant as benign, but evidence is not available for independent evaluation.' The evidence for this variant shows: ClinVar reports it as Likely benign from two clinical laboratories. Therefore, this criterion is applied at Supporting strength because of the reputable benign assertion without independent evidence.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Supporting: A synonymous variant with no predicted impact on splicing and nucleotide not highly conserved.' The evidence for this variant shows: SpliceAI predicts no splicing impact, but conservation data are unavailable. Therefore, this criterion is not applied due to lack of conservation information.