Variant classification summary

NM_002524.5:c.38G>A

NRAS · NP_002515.1:p.(Gly13Asp) · NM_002524.5

GRCh37: chr1:115258744 C>T · GRCh38: chr1:114716123 C>T

Gene: NRAS Transcript: NM_002524.5

Final call

Likely Pathogenic

PS1 strong PS2 moderate PM1 moderate

Variant details

Gene

NRAS

Transcript

NM_002524.5

Protein

NP_002515.1:p.(Gly13Asp)

gnomAD AF

6.195702412978262e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 strong: prior disease reports document the same activating NRAS p.Gly13Asp amino-acid change.

2

PS2 moderate: one constitutional case was absent in both parents, confirming a de novo occurrence.

3

PM1 moderate: residue 13 lies within the approved P-loop domain spanning amino acids 10-17.

Final determination: Rule11 of the ClinGen RASopathy Expert Panel NRAS Version 2.3 framework is satisfied by one Pathogenic Strong criterion (PS1) and one or more Pathogenic Moderate criteria (PS2 and PM1), yielding 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	Not applicable: the VCEP marks PVS1 as not applicable, and NM_002524.5:c.38G>A is a missense substitution producing p.(Gly13Asp).	cspec pvs1_variant_assessment
PS1	Met	Met at Strong: prior disease reports document the same activating NRAS p.Gly13Asp (p.G13D) amino-acid change in JMML and a germ-line RASopathy context.	cspec PMID:19775298 PMID:17332249
PS2	Met	Met at Moderate: one reported constitutional NRAS c.38G>A case was absent in both parents, providing 1 PS2 point under the VCEP scale.	cspec PMID:19775298
PS3	Not assessed	Not assessed: no NRAS G13D-specific assay result is documented; G13D appears only in HRAS validation-control columns, not as an NRAS variant assay result.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:17332249 PMID:19775298
PS4	Not assessed	Not assessed: exact-variant cases are reported, but the VCEP-defined PS4 point total and case-control counts needed to reach ≥1 point are unavailable.	cspec PMID:17332249 PMID:19775298 PMID:18375819
PM1	Met	Met at Moderate: NRAS residue 13 falls within the VCEP-approved P-loop PM1 domain spanning amino acids 10-17.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	Not met: the variant is present at 1/251492 alleles in gnomAD v2.1 and 1/1614022 in v4.1, rather than absent.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the NRAS VCEP explicitly designates PM3 as not applicable, regardless of available phase or affected-proband observations.	cspec
PM4	N/A	Not applicable: c.38G>A produces p.(Gly13Asp), a missense substitution with no insertion, deletion, stop-loss, or protein-length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no verified alternate likely pathogenic amino-acid change at NRAS codon 13 is available for comparison under the VCEP PM5 rule.	cspec
PM6	Not assessed	Not assessed: the available de novo report includes parental absence, so no separate assumed-de-novo observation is available for PM6.
PP1	Not assessed	Not assessed: no informative meioses or familial segregation data are reported for NRAS c.38G>A.
PP2	N/A	Not applicable: the NRAS VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: REVEL 0.699 is below the VCEP PP3 missense threshold of ≥0.7, and SpliceAI's maximum delta score is only 0.009.	cspec revel spliceai
PP4	N/A	Not applicable: the NRAS VCEP explicitly designates PP4 as Not Applicable.	cspec
PP5	N/A	Not applicable: the NRAS VCEP explicitly designates PP5 as Not Applicable, regardless of reported literature or ClinVar assertions.	cspec
BA1	Not met	Not met: gnomAD maximum frequency is 0.00992%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD frequency is 0.00992%, below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows 0 homozygotes, but no healthy-individual observation or VCEP BS2 point assignment is available.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the NRAS VCEP marks BS3 not applicable, and its approved assay table specifies BS3_NA for the relevant pathway assays.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative non-segregating meiosis is reported for the NRAS c.38G>A variant.
BP1	N/A	Not applicable: this is a missense variant, while the VCEP BP1 rule is restricted to specified truncating variant types.	cspec
BP2	Not assessed	Not assessed: the report shows a de novo heterozygous NRAS variant but provides no documented second pathogenic NRAS variant in cis or trans or BP2 point assignment.	cspec PMID:19775298
BP3	N/A	Not applicable: the VCEP explicitly marks BP3 as not applicable for NRAS in Version 2.3.	cspec
BP4	Not met	Not met: REVEL 0.699 exceeds the VCEP BP4 missense cutoff of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no VCEP BP5 point total is available to compare with the governing ≥(-4), ≥(-2), or ≥(-1) thresholds.	cspec
BP6	N/A	Not applicable: the NRAS VCEP explicitly designates BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: NM_002524.5:c.38G>A is a missense exonic variant, whereas BP7 covers synonymous, noncanonical intronic, or non-coding variants.	cspec

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