Variant classification summary

NM_002524.4:c.159G>A

NRAS · NP_002515.1:p.(Leu53=) · NM_002524.4

GRCh37: chr1:115256552 C>T · GRCh38: chr1:114713931 C>T

Gene: NRAS Transcript: NM_002524.4

Final call

Benign

BA1 stand-alone benign BS1 strong BP6 supporting benign BP7 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Leu53=)

gnomAD AF

1.7730263589918702e-05 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NRAS c.159G>A (p.Leu53=) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel.

2

This variant is present in gnomAD, with the highest observed East Asian allele frequency of 0.12545% in v2.1 and 0.06181% in v4.1, which are above the NRAS RASopathy BA1 threshold of 0.05% and BS1 threshold of 0.025%.

3

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.04, supporting no expected RNA effect.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	The NRAS RASopathy specification marks PVS1 as not applicable for this variant, and this synonymous change is not a nonsense, frameshift, or canonical splice-site variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This criterion is intended for an established pathogenic amino acid substitution, but this variant does not change the amino acid sequence.	cspec
PS2	Not assessed	No confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was identified for this variant, so PS2 cannot be assigned from the available evidence.	clinvar cspec
PS3	Not assessed	No variant-specific approved functional study was identified for this synonymous variant, so PS3 cannot be applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	No affected-proband count or case enrichment data were identified for this exact variant, so PS4 cannot be scored.	clinvar gnomad_v2 gnomad_v4 cspec
PM1	Not met	This variant is at codon 53, which is outside the NRAS PM1 domains defined by the RASopathy specification, and no statistically significant hotspot evidence was identified for this site.	cspec vcep_alignment_with_pm1_domains_pptx hotspots
PM2	Not met	This variant is present in gnomAD and therefore is not absent from controls, so PM2_Supporting is not met.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable under the NRAS RASopathy specification.	cspec
PM4	N/A	This synonymous substitution does not change protein length or alter the reading frame, so PM4 does not apply.	cspec
PM5	N/A	The NRAS PM5 rule is classic same-residue missense logic, but this variant is synonymous rather than missense.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo report without full parental confirmation was identified for this variant, so PM6 cannot be assigned.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	clinvar cspec
PP2	N/A	PP2 is not applicable under the NRAS RASopathy specification.	cspec
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and no REVEL, BayesDel, or HCI prior result was available for this synonymous variant.	spliceai cspec
PP4	N/A	PP4 is not applicable under the NRAS RASopathy specification.	cspec
PP5	N/A	PP5 is not applicable under the NRAS RASopathy specification.	cspec
BA1	Met	Population frequency exceeds the NRAS RASopathy BA1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BA1 threshold of 0.05%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Met	Population frequency exceeds the NRAS RASopathy BS1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BS1 threshold of 0.025%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No healthy adult carrier observations meeting the RASopathy point-based BS2 framework were identified for this variant.	cspec
BS3	N/A	BS3 is not applicable under the NRAS RASopathy specification.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 cannot be applied.	clinvar cspec
BP1	N/A	The NRAS RASopathy BP1 rule is intended for truncating or other loss-of-function variants in a gain-of-function disease setting, and this variant is a synonymous substitution.	cspec
BP2	Not assessed	No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant or establishing an alternative molecular explanation under the RASopathy point-based framework.	cspec
BP3	N/A	BP3 is not applicable under the NRAS RASopathy specification.	cspec
BP4	N/A	The NRAS RASopathy BP4 rule is specified for missense variants with REVEL 0.3 or lower, but this variant is synonymous rather than missense.	cspec
BP5	Not assessed	No evidence was identified for another molecular finding that would better explain the phenotype, so BP5 cannot be assigned.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Met	This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting BP7.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.