Classification rationale

BP4BS1BP6 Likely Benign

PTPN11 c.1662G>A

The PTPN11 NM_001330437.1:c.1662G>A (p.(Ala554=)) variant has been reported in ClinVar as Benign, including an expert panel Benign assertion from the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in gnomAD, and its filtering allele frequency exceeds the PTPN11 RASopathy VCEP BS1 threshold of 0.025% in both datasets, with grpmax FAF 0.067298% in gnomAD v2.1 and 0.043105% in gnomAD v4.1.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.18, which supports benign computational evidence rather than a pathogenic splicing effect.³

BP4 + BS1 + BP6 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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 · 14 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

BS1 strong Benign

This variant exceeds the RASopathy VCEP BS1 filtering allele frequency threshold of 0.025% in both available gnomAD datasets. The grpmax FAF is 0.067298% in gnomAD v2.1 and 0.043105% in gnomAD v4.1, both above the BS1 threshold, so BS1 is met at strong strength.

gnomAD v2.1 grpmax FAF 0.00067298 (0.067298%).gnomAD v4.1 grpmax FAF 0.00043105 (0.043105%).

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting Benign

Available computational evidence supports no meaningful effect on splicing. SpliceAI predicts no significant splice impact with a maximum delta score of 0.18, which supports BP4 at supporting strength.

SpliceAI DS_AG 0.04DS_AL 0.18DS_DG 0.00

spliceai ↗cspec ↗

BP6 supporting Benign

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

PTPN11 criteria specification marks BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied from the available evidence.

PS3 No variant-specific approved functional study showing a damaging effect on protein function or splicing was identified, so PS3 was not applied.

PS4 No case-control enrichment or exact affected-case count meeting the RASopathy VCEP point-based PS4 thresholds was identified, so PS4 was not applied.

PM1 Available evidence does not place this variant in a PTPN11 critical residue or established hotspot used for PM1.

PM2 This variant is not absent from population databases.

PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not applied.

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

PP3 Available computational evidence does not support a damaging effect.

Benign

BA1 The stand-alone benign threshold was not met consistently across the available gnomAD datasets.

BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals for BS2, so BS2 was not applied.

BS4 No segregation study showing lack of segregation with disease was identified, so BS4 was not applied.

BP2 No phase data or co-occurrence with another pathogenic variant were identified, so BP2 was not applied.

BP5 No alternative molecular diagnosis explaining the phenotype was identified, so BP5 could not be assessed from the available evidence.

BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.18.

N/A · 11 PVS1 · PS1 · PM3 · PM4 · PM5 · 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= 2.85051e-05; MAF= 0.00285%, 46/1613744 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00058345; MAF= 0.05835%, 35/59988 alleles, homozygotes = 0); grpmax FAF= 0.00043105.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000139413; MAF= 0.01394%, 35/251052 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000925123; MAF= 0.09251%, 32/34590 alleles, homozygotes = 0); grpmax FAF= 0.00067298.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0029% · 46 / 1,613,744
0 hom · FAF 0.043%

Admixed American 35 / 59,988	0.058%
Remaining individuals 2 / 62,468	0.0032%
East Asian 1 / 44,894	0.0022%
South Asian 1 / 91,070	0.0011%
European (non-Finnish) 7 / 1,179,846	0.00059%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.014% · 35 / 251,052
0 hom · FAF 0.067%

Admixed American 32 / 34,590	0.093%
East Asian 2 / 18,392	0.011%
European (non-Finnish) 1 / 113,360	0.00088%

+ 5 not observed (African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (2 clinical laboratories) 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 = 0.18).

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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