Variant classification summary

NM_002524.4:c.71T>A

NRAS · NP_002515.1:p.(Ile24Asn) · NM_002524.4

GRCh37: chr1:115258711 A>T · GRCh38: chr1:114716090 A>T

Gene: NRAS Transcript: NM_002524.4

Final call

Likely Pathogenic

PS3 supporting PS4 moderate PM2 supporting PM6 strong PP3 supporting PP5 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Ile24Asn)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NRAS c.71T>A (p.Ile24Asn) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen RASopathy expert panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the NRAS RASopathy framework.

3

In expert-panel-reviewed functional evidence, RAS activation assays showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition, supporting an abnormal gain-of-function effect.

4

Computational evidence supports a damaging missense effect, with REVEL 0.863 above the PP3 threshold of 0.7, SpliceAI showing no significant splice impact with a maximum delta score of 0.00, and BayesDel 0.159947.

Final determination: Rule11 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 Likely Pathogenic.

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	This is a missense substitution, and the NRAS RASopathy specification marks PVS1 as not applicable for this gene-disease framework. The generic PVS1 scaffold also indicates that this variant is not a null variant eligible for PVS1 assessment.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No reviewed evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change in the permitted NRAS RASopathy framework.	cspec
PS2	Not met	Available evidence describes de novo occurrences with unconfirmed parental relationships, so confirmed maternity and paternity were not established for PS2.	clinvar cspec
PS3	Met	In expert-panel-reviewed functional evidence, RAS activation assays in 293T cells showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition. This supports an abnormal gain-of-function effect consistent with the NRAS RASopathy mechanism.	clinvar vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Met	This variant has been reported in 4 probands with features of RASopathy in expert-panel-reviewed evidence, which the NRAS RASopathy expert panel used to apply PS4 at Moderate strength.	clinvar cspec
PM1	Not met	Residue 24 is outside the NRAS RASopathy PM1 domains defined for this specification: P-loop amino acids 10-17 and Switch I amino acids 25-40, as well as SW2 amino acids 57-64 and SAK amino acids 145-156. Therefore this missense change does not meet the domain-based PM1 rule.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the NRAS RASopathy requirement for PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this NRAS RASopathy framework because the relevant disease context is not recessive.	cspec
PM4	N/A	PM4 is intended for in-frame insertions or deletions and stop-loss variants causing protein length change. This variant is a missense substitution and does not change protein length.	cspec
PM5	Not assessed	No reviewed evidence was identified confirming a different pathogenic or likely pathogenic amino acid substitution at this same codon within the permitted RASopathy framework, so PM5 was not applied from the currently reviewed sources.	cspec
PM6	Met	Expert-panel-reviewed evidence reports this variant as de novo in 2 individuals with features of RASopathy, but with unconfirmed parental relationships. Under the NRAS RASopathy point-based framework, this was used to apply PM6 at Strong strength.	clinvar cspec
PP1	Not assessed	No segregation data were identified to show that this variant co-segregates with RASopathy across informative meioses.	cspec
PP2	N/A	PP2 is not applicable in the NRAS RASopathy specification.	cspec
PP3	Met	For this missense variant, the REVEL score is 0.863, which is above the NRAS RASopathy PP3 threshold of 0.7. SpliceAI predicts no splice effect with a maximum delta score of 0.00, supporting interpretation as a missense effect rather than a splicing mechanism. BayesDel is 0.159947 and does not contradict a damaging missense interpretation.	revel spliceai bayesdel cspec
PP4	N/A	PP4 is not applicable in this NRAS RASopathy framework because phenotype-specific evidence is handled through other criteria such as PS4.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD, which is below the BA1 threshold of at least 0.05% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD, which is below the BS1 threshold of at least 0.025% filtering allele frequency.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals at a level sufficient for BS2 under the NRAS RASopathy point-based framework.	cspec
BS3	N/A	BS3 is not applicable in this NRAS RASopathy specification.	cspec
BS4	Not assessed	No non-segregation data were identified to show that this variant fails to track with disease in informative relatives.	cspec
BP1	N/A	BP1 in this framework is reserved for truncating loss-of-function variants in a gain-of-function RASopathy gene without an established loss-of-function disease correlation. This variant is a missense substitution, so BP1 does not apply.	cspec
BP2	Not assessed	No evidence was identified showing this variant in cis or trans with an alternative pathogenic molecular explanation sufficient for BP2 point assignment.	cspec
BP3	N/A	BP3 is not applicable in this NRAS RASopathy specification.	cspec
BP4	Not met	BP4 is not met because the REVEL score is 0.863, which is above the benign-supporting threshold of 0.3 or lower for missense variants. Although SpliceAI predicts no splice impact with a maximum delta score of 0.00, the missense predictor result does not support a benign interpretation.	revel spliceai bayesdel cspec
BP5	Not assessed	No evidence was identified showing an alternative molecular explanation in a different gene or a phenotype fully explained by another cause sufficient for BP5 point assignment.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply.	cspec spliceai

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