Classification rationale

BA1BS1BP4BP6 Benign

PTPN11 c.526-8C>A

The PTPN11 NM_001330437.1:c.526-8C>A (NP_001317366.1:p.?) variant has been reported in ClinVar and is classified as Benign by the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in gnomAD v2.1 at 0.06730% and in gnomAD v4.1 at 0.13022%, which are both above the PTPN11 BA1 threshold of 0.05% and the BS1 threshold of 0.025%.² SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, which supports BP4 and does not support PP3 for a splice-region effect.³

BA1 + BS1 + BP4 + BP6 → 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 · 4 applied · 12 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone review Benign

This variant exceeds the PTPN11 BA1 population threshold of 0.05%. It is present in gnomAD v2.1 at AF 0.06730% and in gnomAD v4.1 at AF 0.13022%, both above the BA1 threshold.

gnomAD v2.1 total AF 0.06730%gnomAD v4.1 total AF 0.13022%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong review Benign

This variant exceeds the PTPN11 BS1 population threshold of 0.025%. It is present in gnomAD v2.1 at AF 0.06730% and in gnomAD v4.1 at AF 0.13022%, both above the BS1 threshold.

gnomAD v2.1 total AF 0.06730%gnomAD v4.1 total AF 0.13022%

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP4 supporting review Benign

Computational evidence supports no meaningful splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, which is consistent with a negligible predicted effect for this non-canonical intronic variant.

SpliceAI max delta score 0.06DS_AG 0.06DS_AL 0.00

spliceai ↗cspec ↗

BP6 supporting review Benign

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

BP6 marked not applicable in the PTPN11 specificationClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 2 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo observation with documented parental testing and phenotype information was identified for this variant.

PS3 No published RNA study, minigene assay, or other approved functional assay specific to this variant was identified.

PS4 Although this variant has been submitted to ClinVar, no case-count or enrichment data were identified to meet the RASopathy point-based PS4 thresholds.

PM2 This variant is not absent from population databases.

PM6 No presumed de novo report without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a deleterious splicing effect.

Benign

BS2 No case-level evidence was identified showing this variant in unaffected individuals at the point threshold required by the RASopathy specification.

BS4 No non-segregation data were identified for this variant.

BP2 No phase data or alternate molecular explanation data were identified to support BP2 scoring.

BP5 No independent molecular diagnosis or alternate cause data were identified to support BP5 scoring.

BP7 This non-canonical intronic variant has a low SpliceAI score, but no conservation evidence was identified to confirm the full BP7 requirements.

N/A · 12 PVS1 · PS1 · PM1 · 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= 0.00130217; MAF= 0.13022%, 2078/1595796 alleles, homozygotes = 4) and has highest observed frequency in the European (non-Finnish) population (AF= 0.001701; MAF= 0.17010%, 1980/1164018 alleles, homozygotes = 2); grpmax FAF= 0.00163779.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000673019; MAF= 0.06730%, 190/282310 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00129804; MAF= 0.12980%, 167/128656 alleles, homozygotes = 0); grpmax FAF= 0.00111834.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.13% · 2078 / 1,595,796
4 hom · FAF 0.16%

European (non-Finnish) 1980 / 1,164,018	0.17% 2 hom
Remaining individuals 57 / 61,836	0.092% 1 hom
African/African American 25 / 74,664	0.033%
Admixed American 9 / 59,958	0.015%
European (Finnish) 7 / 64,016	0.011% 1 hom

+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.067% · 190 / 282,310
1 hom · FAF 0.11%

European (non-Finnish) 167 / 128,656	0.13%
Remaining individuals 5 / 7,208	0.069%
African/African American 7 / 24,968	0.028%
Admixed American 8 / 35,434	0.023%
European (Finnish) 3 / 25,122	0.012% 1 hom

+ 3 not observed (Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (12 clinical laboratories) and as Likely benign (9 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 36709)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV105261528, n = 1 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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