Variant classification summary

NM_002524.4:c.112-8A>G

NRAS · NP_002515.1:p.? · NM_002524.4

GRCh37: chr1:115256607 T>C · GRCh38: chr1:114713986 T>C

Gene: NRAS Transcript: NM_002524.4

Final call

Likely Benign

BS1 strong BP6 supporting benign

Variant details

Gene

NRAS

Transcript

NM_002524.4

Protein

NP_002515.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NRAS c.112-8A>G (p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and expert panel review is present.

2

This variant is present in population databases, with gnomAD v2.1 total AF 0.02558% and grpmax FAF 0.03711%, and gnomAD v4.1 total AF 0.03946% and grpmax FAF 0.04727%, which is above the NRAS RASopathy BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.

3

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.02, which does not support a deleterious splicing prediction.

Final determination: Rule20 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 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	This intronic variant is at c.112-8 and does not affect a canonical +/-1 or +/-2 splice site. The NRAS RASopathy specification marks PVS1 as not applicable for this gene framework, and the generic PVS1 scaffold does not place this variant in a default null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This criterion is for the same amino acid change as a previously established pathogenic variant. This variant is intronic with no defined amino acid substitution, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity established was identified. Available evidence does not provide the case-level trio data required for PS2 point assignment.	cspec clinvar
PS3	Not assessed	No approved functional or RNA assay result for this specific splice-region variant was identified. Available evidence therefore does not support applying PS3.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not met	This variant is present in population databases and no affected-case enrichment data were identified. Available evidence does not show the case-count excess required for PS4.	cspec gnomad_v2 gnomad_v4 clinvar
PM1	N/A	PM1 in the NRAS RASopathy specification applies to established protein functional domains such as the P-loop, SW1, SW2, and SAK. This variant is an intronic splice-region change and does not map to a protein residue within those domains.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	PM2_Supporting requires absence from gnomAD. This variant is present in gnomAD v2.1 at AF 0.02558% (71/277542) and in gnomAD v4.1 at AF 0.03946% (529/1340490), so the absence threshold is not met.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the NRAS RASopathy specification.	cspec
PM4	N/A	PM4 applies to in-frame insertions or deletions and stop-loss variants. This variant is a noncoding intronic substitution, so PM4 is not applicable.	cspec
PM5	N/A	PM5 is for a novel missense change at a residue where a different pathogenic missense change has been seen. This variant is intronic with no codon substitution, so PM5 is not applicable.	cspec
PM6	Not assessed	No assumed de novo report for this variant was identified. Available evidence does not provide the case-level inheritance information required for PM6 point assignment.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not provide informative meioses to support PP1.	cspec clinvar
PP2	N/A	PP2 is not applicable in the NRAS RASopathy specification.	cspec
PP3	Not met	For splice prediction, PP3 requires a predicted splicing outcome that matches the disease mechanism. SpliceAI shows a maximum delta score of 0.02, which predicts no significant splice impact. REVEL and BayesDel are not available for this intronic variant. Available computational evidence therefore does not support PP3.	cspec spliceai
PP4	N/A	PP4 is not applicable in the NRAS RASopathy specification.	cspec
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BA1	Not met	BA1 requires a gnomAD filtering allele frequency of at least 0.05%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both below the 0.05% threshold, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Met	BS1 requires a gnomAD filtering allele frequency of at least 0.025%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both above the 0.025% threshold, so BS1 is met at strong strength.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Although this variant is present in population databases, no phenotype-qualified healthy adult observations or point-based evidence meeting the RASopathy BS2 specification were identified. Available evidence is insufficient to apply BS2.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in the NRAS RASopathy specification.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant. Available evidence does not support BS4.	cspec
BP1	N/A	In this framework, BP1 is used for truncating or canonical splice variants in a gene where gain-of-function missense variants cause disease. This variant is a noncanonical intronic change at c.112-8, so BP1 is not applicable.	cspec
BP2	Not assessed	No evidence was identified that this variant occurs in cis or trans with another established pathogenic RASopathy variant or that the required point-based alternative-molecular-cause framework is satisfied. BP2 cannot be applied from the available evidence.	cspec
BP3	N/A	BP3 is not applicable in the NRAS RASopathy specification.	cspec
BP4	N/A	In this framework, BP4 is defined for missense variants with REVEL <=0.3. This variant is intronic rather than missense, and no REVEL or BayesDel score is available, so BP4 is not applicable.	cspec spliceai
BP5	Not assessed	No alternative molecular explanation for the phenotype in another gene, and no phenotype-based evidence against this variant, were identified. Available evidence is insufficient to apply BP5.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not assessed	This noncanonical intronic variant has a low SpliceAI maximum delta score of 0.02, which predicts no significant splice impact. However, the BP7 specification also requires that the nucleotide not be highly conserved, and no conservation evidence was identified, so BP7 is not applied.	cspec spliceai

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