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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.53A>G
p.Asn18Ser  ·  PTPN11
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Classification rationale
1

The PTPN11 c.53A>G (p.Asn18Ser) variant has not been observed in COSMIC and has been reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel, with additional benign and likely benign clinical laboratory submissions.

clinvar ↗
2

This variant is present in gnomAD v2.1 and v4.1, with the highest observed South Asian frequency reaching 0.09552% in v4.1 and grpmax filtering allele frequencies of 0.05125% in v2.1 and 0.07930% in v4.1, which are above the PTPN11 RASopathy BA1 threshold of 0.05%.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource.

4

Computational evidence does not meet the PTPN11 missense thresholds for either PP3 or BP4: REVEL is 0.301, which is below the PP3 cutoff of 0.7 and just above the BP4 cutoff of 0.3, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.292277.

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 9.54464e-05; MAF= 0.00954%, 24/251450 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000751241; MAF= 0.07512%, 23/30616 alleles, homozygotes = 0); grpmax FAF= 0.00051247.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 5.57597e-05; MAF= 0.00558%, 90/1614070 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000955183; MAF= 0.09552%, 87/91082 alleles, homozygotes = 1); grpmax FAF= 0.00079302.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 135112)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.301. BayesDel score = -0.292277.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueN18
Hotspots ↗