Classification rationale

BA1BS1BP6 Benign

PTPN11 c.1221A>G

The PTPN11 c.1221A>G (p.Gly407=) variant has not been identified in a statistically significant somatic hotspot and has been reported in ClinVar as Benign, including a benign expert-panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.¹ In gnomAD, this variant exceeds the PTPN11 RASopathy benign population thresholds, with grpmax filtering allele frequencies of 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold of 0.05% and the BS1 threshold of 0.025%.² This synonymous variant does not change the encoded amino acid, and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02.³

BA1 + BS1 + BP6 → Benign

1 hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001330437.1 · variants mapped to exon structure

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant exceeds the PTPN11 RASopathy BA1 filtering allele frequency threshold of 0.05%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold.

gnomAD v2.1 grpmax FAF 0.11284%gnomAD v4.1 grpmax FAF 0.13502%BA1 threshold 0.05000%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong Benign

This variant exceeds the PTPN11 RASopathy BS1 filtering allele frequency threshold of 0.025%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BS1 threshold.

gnomAD v2.1 grpmax FAF 0.11284%gnomAD v4.1 grpmax FAF 0.13502%BS1 threshold 0.02500%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

PTPN11 VCEP lists BP6 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS1 This variant does not change the encoded amino acid, so it does not match a previously established pathogenic amino acid substitution.

PS2 No confirmed de novo occurrence with phenotype and parental relationship data was identified in the available sources, so the PS2 point-based de novo criterion could not be assessed.

PS3 No approved functional assay result specific to this synonymous variant was identified in the available RASopathy VCEP functional study materials, so PS3 was not assessed.

PS4 The available sources did not provide deduplicated affected proband counts or case-control enrichment data for this exact variant, so the PTPN11 PS4 point-based criterion could not be assessed.

PM1 Codon 407 is not among the PTPN11 RASopathy VCEP PM1 residues, and available hotspot review did not identify a statistically significant hotspot at G407, so PM1 is not met.

PM2 This variant is not absent from population databases.

PM5 This synonymous variant does not create an amino acid substitution at codon 407, so it does not meet the PTPN11 same-codon missense rule.

PM6 No assumed de novo report with sufficient variant-specific family detail was identified, so PM6 could not be assessed.

PP1 No segregation data were identified for this variant, so PP1 could not be assessed.

PP3 Available computational evidence does not support a deleterious effect.

Benign

BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals, so BS2 was not assessed.

BS4 No family data showing lack of segregation were identified for this variant, so BS4 could not be assessed.

BP2 No phase data were identified showing this variant with another pathogenic variant in cis or trans, so BP2 was not assessed.

BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02.

BP5 No evidence was identified showing that this variant occurs in a case with a fully alternate molecular explanation sufficient for the RASopathy BP5 point system, so BP5 was not assessed.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02.

N/A · 9 PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.11228e-05; MAF= 0.00911%, 147/1613208 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00155945; MAF= 0.15594%, 142/91058 alleles, homozygotes = 0); grpmax FAF= 0.00135023.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000186931; MAF= 0.01869%, 47/251430 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00147001; MAF= 0.14700%, 45/30612 alleles, homozygotes = 0); grpmax FAF= 0.00112836.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0091% · 147 / 1,613,208
0 hom · FAF 0.14%

South Asian 142 / 91,058	0.16%
Remaining individuals 4 / 62,448	0.0064%
European (non-Finnish) 1 / 1,179,334	8.5e-05%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.019% · 47 / 251,430
0 hom · FAF 0.11%

South Asian 45 / 30,612	0.15%
Remaining individuals 1 / 6,136	0.016%
Admixed American 1 / 34,592	0.0029%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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