Variant classification summary

NM_002524.4:c.31G>A

NRAS · NP_002515.1:p.(Ala11Thr) · NM_002524.4

GRCh37: chr1:115258751 C>T · GRCh38: chr1:114716130 C>T

Gene: NRAS Transcript: NM_002524.4

Final call

VUS

PM1 moderate

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.(Ala11Thr)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NRAS c.31G>A (p.Ala11Thr) variant has been reported in ClinVar with an expert panel interpretation of uncertain significance and has also been curated in variant-specific cancer resources.

2

This variant is present at very low frequency in population databases, with 1/251492 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613858 alleles in gnomAD v4.1 (AF 0.000062%).

3

The p.Ala11Thr change lies within the NRAS P-loop (amino acids 10-17), a RASopathy VCEP-specified critical functional domain, which supports PM1.

4

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.00), the REVEL score is 0.412, and the BayesDel score is 0.00411725; these values do not meet the RASopathy VCEP thresholds for either PP3 or BP4.

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 variant is a missense substitution, not a null variant, and it does not fall into the default PVS1 categories of nonsense, frameshift, or canonical +/-1,2 splice variants.	cspec pvs1_variant_assessment
PS1	Not met	Available evidence does not identify a previously established pathogenic variant with the same amino acid change that would support PS1.	cspec
PS2	Not assessed	No confirmed de novo occurrence with documented maternity and paternity confirmation was identified for this variant.	cspec clinvar
PS3	Not met	Published functional literature was identified, but the available materials do not provide a reviewed result from one or more RASopathy VCEP-approved assays for this exact variant that is sufficient to apply PS3.	oncokb PMID:34117033 vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	This variant has been reported in ClinVar, but no secure count of unrelated affected individuals with this exact variant or case-control enrichment data was identified to support PS4 scoring.	cspec clinvar
PM1	Met	This missense variant affects NRAS residue Ala11, which lies within the P-loop region (amino acids 10-17), a RASopathy VCEP-specified critical and well-established functional domain; this supports PM1 at Moderate strength.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/251492 alleles (AF 0.00040%) and in gnomAD v4.1 at 1/1613858 alleles (AF 0.000062%), so the RASopathy VCEP PM2 absence requirement is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this RASopathy VCEP framework for this case.	cspec
PM4	Not met	This variant is a missense substitution and does not cause a protein length change, so PM4 is not met.	cspec
PM5	Not met	Available evidence does not identify a different pathogenic or likely pathogenic amino acid change at NRAS codon 11 that would support PM5.	cspec
PM6	Not assessed	No presumed de novo occurrence without full parentage confirmation was identified for this variant.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not applicable in this RASopathy VCEP framework.	cspec
PP3	Not met	For missense variants, the RASopathy VCEP applies PP3 when REVEL is at least 0.7. The REVEL score for this variant is 0.412, which is below that threshold. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available computational data do not support PP3.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in this RASopathy VCEP framework.	cspec
PP5	N/A	PP5 is not applicable in this RASopathy VCEP framework.	cspec
BA1	Not met	The RASopathy VCEP BA1 threshold is a filtering allele frequency of at least 0.05%. This variant is far below that threshold, with gnomAD frequencies of 0.00040% in v2.1 and 0.000062% in v4.1, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The RASopathy VCEP BS1 threshold is a filtering allele frequency of at least 0.025%. This variant is well below that threshold, with gnomAD frequencies of 0.00040% in v2.1 and 0.000062% in v4.1, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of apparently unaffected individuals to support BS2.	cspec
BS3	N/A	BS3 is not applicable in this RASopathy VCEP framework.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	In this RASopathy VCEP framework, BP1 is intended for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanisms. This variant is missense, so BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified that this variant occurred with an alternative molecular explanation in cis or trans that would support BP2 scoring.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy VCEP framework.	cspec
BP4	Not met	For missense variants, the RASopathy VCEP applies BP4 when REVEL is 0.3 or lower. The REVEL score for this variant is 0.412, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice effect with a maximum delta score of 0.00, but that does not overcome the missense REVEL threshold requirement.	cspec revel spliceai bayesdel
BP5	Not assessed	No evidence was identified for an alternative molecular cause that would explain the phenotype and support BP5 scoring.	cspec
BP6	N/A	BP6 is not applicable in this RASopathy VCEP framework.	cspec
BP7	N/A	This variant is missense rather than synonymous or intronic, so BP7 is not applicable.	cspec spliceai

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