NM_002524.4:c.368G>A

NRAS · NP_002515.1:p.(Arg123Lys) · NM_002524.4

GRCh37: chr1:115252272 C>T · GRCh38: chr1:114709651 C>T

Gene: NRAS Transcript: NM_002524.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Arg123Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The NRAS c.368G>A (p.Arg123Lys) variant has not been observed in COSMIC and is reported in ClinVar as uncertain significance, including an expert panel submission from the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the NRAS RASopathy VCEP PM2_Supporting rule.

The reviewed RASopathy VCEP functional study materials identify approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported.

In silico evidence supports a deleterious missense effect, with REVEL 0.759 above the NRAS RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.166482 directionally consistent with a damaging prediction, and SpliceAI predicting no significant splice impact with a maximum delta score of 0.00.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 variant, and the NRAS RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this change does not fall into a null-variant category such as nonsense, frameshift, or canonical splice-site loss.	cspec pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant producing the same amino acid change, p.Arg123Lys, was identified in the reviewed evidence, so PS1 is not supported.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence.	cspec clinvar
PS3	Not assessed	The reviewed RASopathy VCEP functional study materials list approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	This variant is absent from gnomAD, satisfying the PM2 prerequisite for PS4 consideration, but no usable count of unrelated affected individuals or point-based case evidence was identified, so PS4 cannot be assessed.	cspec gnomad_v2 gnomad_v4 clinvar
PM1	Not met	Residue Arg123 is outside the NRAS RASopathy VCEP PM1 domains (P-loop amino acids 10-17, Switch I amino acids 25-40, Switch II amino acids 57-64, and SAK amino acids 145-156), so PM1 is not met.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 threshold requiring absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the NRAS RASopathy VCEP framework.	cspec
PM4	N/A	This is a missense substitution and does not cause an in-frame insertion, in-frame deletion, or stop-loss change, so PM4 is not applicable.	cspec
PM5	Not met	No different pathogenic or likely pathogenic missense change at codon 123 was identified in the reviewed evidence, so PM5 is not supported.	cspec clinvar
PM6	Not assessed	No unconfirmed de novo report with sufficient phenotype context was identified for this variant, so PM6 cannot be assessed from the available evidence.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec clinvar
PP2	N/A	PP2 is not applicable in the NRAS RASopathy VCEP framework.	cspec
PP3	Met	Computational evidence supports a deleterious effect. REVEL is 0.759, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score is 0.166482, which is directionally consistent with a damaging missense prediction.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in the NRAS RASopathy VCEP framework because phenotype-based evidence is handled through other criteria such as PS4.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BA1 threshold of 0.05%, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BS1 threshold of 0.025%, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not met	No observations of this variant in unaffected individuals suitable for NRAS RASopathy VCEP BS2 scoring were identified, so BS2 is not met.	cspec clinvar
BS3	N/A	BS3 is not applicable in the NRAS RASopathy VCEP framework.	cspec
BS4	Not assessed	No non-segregation data or unaffected carrier relatives were identified for this variant, so BS4 cannot be assessed.	cspec clinvar
BP1	N/A	BP1 in the NRAS RASopathy VCEP framework is reserved for truncating or other loss-of-function variant types in genes where gain-of-function missense variants are the primary disease mechanism. This variant is missense, so BP1 is not applicable.	cspec pvs1_variant_assessment
BP2	Not assessed	No evidence was identified that this variant occurs in cis or trans with an alternative pathogenic RASopathy variant with sufficient phenotype context, so BP2 cannot be assessed.	cspec clinvar
BP3	N/A	BP3 is not applicable in the NRAS RASopathy VCEP framework.	cspec
BP4	Not met	Computational evidence does not support a benign interpretation. REVEL is 0.759, which is above the NRAS RASopathy VCEP BP4 benign threshold of 0.3, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score of 0.166482 does not provide benign support.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternative molecular explanation or phenotype-discordant diagnosis was identified that would support BP5, so this criterion cannot be assessed.	cspec clinvar
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable.	cspec spliceai

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