About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.53A>G, p.(Asn18Ser)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PTPN11 VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant meets the benign stand-alone population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BA1 threshold of 0.05%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above the same threshold.
BS1Strong
BS1 · strong
This variant exceeds the BS1 population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BS1 threshold of 0.025%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above this threshold.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong benign, BP6 supporting benign; maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
90 / 1,614,070 alleles
gnomAD v4.1: 90 / 1,614,070 alleles. Recorded AF 5.57597e-05. Recorded homozygote count 1.
gnomAD v2.1
This 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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
8 reported laboratory submissions
5 Benign · 2 Likely benign · 1 Uncertain significance.
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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%.
No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource.
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.
No criteria match.
Met · 3
BA1 Stand aloneThis variant meets the benign stand-alone population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BA1 threshold of 0.05%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above the same threshold. Details ▾Hide ▴
Rule
BA1 applies when gnomAD filtering allele frequency is at least 0.05%.
Evidence considered
- gnomAD v4.1 South Asian AF 0.09552% and grpmax FAF 0.07930%
- gnomAD v2.1 grpmax FAF 0.05125%
Sources
BS1 StrongThis variant exceeds the BS1 population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BS1 threshold of 0.025%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above this threshold. Details ▾Hide ▴
Rule
BS1 applies when gnomAD filtering allele frequency is at least 0.025%.
Evidence considered
- gnomAD v4.1 South Asian AF 0.09552% and grpmax FAF 0.07930%
- gnomAD v2.1 grpmax FAF 0.05125%
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No evidence was identified that this amino acid change matches a previously established pathogenic PTPN11 variant; the available ClinVar record for this change is benign by the ClinGen RASopathy expert panel. Details ▾Hide ▴
PS3 No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource, so functional evidence supporting a damaging effect was not established for PS3. Details ▾Hide ▴
Rule
PS3 supporting requires one approved assay; PS3 moderate requires two or more different approved assays.
Evidence considered
- RASopathy VCEP approved functional study workbook reviewed
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- Direct review of any additional non-approved functional literature could be performed if needed.
Sources
PM1 Residue 18 is not listed among the PTPN11 residues allowed for PM1 in the RASopathy specification, and no hotspot evidence supporting this residue was identified. Details ▾Hide ▴
Rule
Applicable only to specified directly interacting residues between the N-SH2 and PTP domains; not applicable to specific amino acid residues handled by PM5.
Evidence considered
- PTPN11 PM1 residue list reviewed
- Cancer Hotspots search showed no hotspot row for N18
Sources
PM2 This variant is present in population databases, so it is not absent from controls and does not meet PM2_Supporting. Details ▾Hide ▴
Rule
PM2 at supporting strength requires the variant to be absent from gnomAD.
Evidence considered
- gnomAD v2.1 and v4.1 frequencies reviewed
Sources
PM5 No pathogenic or likely pathogenic missense comparator at the same residue was identified, so the available evidence does not support PM5 for codon 18. Details ▾Hide ▴
Rule
PM5 moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5 strong requires two different pathogenic or likely pathogenic residue changes at the same codon observed in at least 5 probands.
Evidence considered
- Classic same-residue PM5 rule reviewed
- available same-residue ClinVar records did not establish a P/LP comparator
Still missing
- If needed
- same-residue comparator review could be repeated directly in ClinVar for confirmation.
Sources
PP3 Computational evidence does not meet the PTPN11 PP3 threshold: REVEL is 0.301, which is below the required threshold of at least 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL at least 0.7; for splicing impact, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.301
- SpliceAI max delta 0.00
- BayesDel score -0.292277
Sources
BP4 Computational evidence does not meet the PTPN11 BP4 threshold because REVEL is 0.301, which is above the benign cutoff of 0.3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.292277, but the panel's missense BP4 rule is not met. Details ▾Hide ▴
Rule
For missense variants, BP4 requires REVEL at or below 0.3.
Evidence considered
- REVEL score 0.301
- SpliceAI max delta 0.00
- BayesDel score -0.292277
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with the case-level details needed for RASopathy point scoring was identified. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: 4 points very strong, 2 points strong, 1 point moderate.
Evidence considered
- ClinVar summary reviewed
- RASopathy de novo point-based rule reviewed
Still missing
- Parental testing details were not available.
- No verified de novo point total was available for PS2 weighting.
Sources
PS4 No validated count of unrelated affected individuals or case-enrichment point total was identified, and the observed population frequency argues against applying PS4 from the currently available evidence. Details ▾Hide ▴
Rule
RASopathy VCEP PS4 uses point-based case enrichment thresholds: at least 1 point supporting, at least 3 points moderate, at least 5 points strong.
Evidence considered
- ClinVar summary reviewed
- gnomAD population frequency reviewed
- RASopathy PS4 point-based rule reviewed
Still missing
- Independent affected-case counts were not available.
- No RASopathy PS4 point total was available.
Sources
PM6 No assumed de novo observation with sufficient case-level detail was identified for PM6 scoring. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: 2 points strong, 1 point moderate, 0.5 point supporting for PM6.
Evidence considered
- ClinVar summary reviewed
- RASopathy de novo point-based rule reviewed
Still missing
- Family testing details were not available.
- No PM6 point total was available.
Sources
PP1 No segregation data with informative meioses were identified for this variant. Details ▾Hide ▴
PP2 The PTPN11 missense z-score needed for PP2 was not identified in the available evidence, so PP2 could not be adjudicated from the reviewed materials. Details ▾Hide ▴
Rule
PP2 applies when the gnomAD missense z score is greater than 3.09.
Evidence considered
- PP2 rule reviewed
Still missing
- Gene-level missense constraint value was not available in the reviewed evidence.
Sources
BS2 Although this variant is present in gnomAD, the evidence reviewed did not establish the number and clinical status of unaffected individuals needed for BS2 point assignment. Details ▾Hide ▴
Rule
BS2 uses RASopathy benign point thresholds.
Evidence considered
- gnomAD v4.1 shows population carriers including 1 homozygote
- RASopathy BS2 point-based rule reviewed
Still missing
- Phenotype information for population carriers was not available.
- No BS2 point total was available.
Sources
BS4 No informative non-segregation data were identified for this variant. Details ▾Hide ▴
BP2 No phase or alternate molecular diagnosis data were identified to support BP2 point scoring. Details ▾Hide ▴
Rule
BP2 uses benign point thresholds under the RASopathy specification.
Evidence considered
- BP2 point-based rule reviewed
Still missing
- Phase information was not available.
- No BP2 point total was available.
Sources
BP5 No alternate molecular explanation or benign point total was identified to support BP5 scoring. Details ▾Hide ▴
Rule
BP5 uses benign point thresholds under the RASopathy specification.
Evidence considered
- BP5 point-based rule reviewed
Still missing
- No BP5 point total was available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, and the PTPN11 RASopathy specification marks PVS1 as not applicable for this criterion assessment. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: PVS1 not applicable; generic scaffold also does not support PVS1 for this missense change.
Evidence considered
- PTPN11 VCEP marks PVS1 not applicable
- generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PM3 VCEPPM3 is not applicable under the PTPN11 RASopathy specification for this evaluation. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: PM3 not applicable.
Evidence considered
- PTPN11 VCEP applicability reviewed
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- variant consequence reviewed
Sources
PP4 VCEPPP4 is not applicable under the PTPN11 RASopathy specification for this evaluation. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: PP4 not applicable.
Evidence considered
- PTPN11 VCEP applicability reviewed
Sources
PP5 VCEPPP5 is not applicable under the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: PP5 not applicable.
Evidence considered
- PTPN11 VCEP applicability reviewed
Sources
BS3 VCEPBS3 is not applicable under the PTPN11 RASopathy specification for this evaluation. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: BS3 not applicable.
Evidence considered
- PTPN11 VCEP applicability reviewed
Sources
BP1 N/ABP1 in this framework is intended for truncating variants in genes without established loss-of-function disease correlation; this variant is missense, so BP1 does not apply. Details ▾Hide ▴
Rule
Use BP1 for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- variant consequence reviewed
- BP1 contraindication text reviewed
Sources
BP3 VCEPBP3 is not applicable under the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 VCEP: BP3 not applicable.
Evidence considered
- PTPN11 VCEP applicability reviewed
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- variant consequence reviewed
- SpliceAI reviewed
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.53A>G
- Protein (HGVS p.)
- NP_001317366.1:p.(Asn18Ser)
- GRCh38
- chr12:112446314 A>G
- GRCh37
- chr12:112884118 A>G
- ClinVar
- 135112
Gene diagram
Every interpreted variant in PTPN11, mapped onto the exon structure of NM_001330437.1. Select a row to find it on the plot.
PTPN11NM_001330437.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTPN11
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
90 / 1,614,070 alleles
AF 5.58e-05 · 1 homozygotes · FAF 0.000793
gnomAD v2.1
24 / 251,450 alleles
AF 9.54e-05 · 0 homozygotes · FAF 0.000512
By genetic ancestry
gnomAD v4.1
AF 5.6e-05 · 90 / 1,614,070 alleles · 1 hom · FAF 0.00079
| South Asian87 / 91,082 | 0.000961 hom |
| Remaining individuals3 / 62,498 | 4.8e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 9.5e-05 · 24 / 251,450 alleles · 0 hom · FAF 0.00051
| South Asian23 / 30,616 | 0.00075 |
| Remaining individuals1 / 6,136 | 0.00016 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This 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 v2.1
This 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.301
- BayesDel
- -0.292
How the predictions were used
PP3 Computational evidence does not meet the PTPN11 PP3 threshold: REVEL is 0.301, which is below the required threshold of at least 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL at least 0.7; for splicing impact, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.301
- SpliceAI max delta 0.00
- BayesDel score -0.292277
Sources
BP4 Computational evidence does not meet the PTPN11 BP4 threshold because REVEL is 0.301, which is above the benign cutoff of 0.3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.292277, but the panel's missense BP4 rule is not met. Details ▾Hide ▴
Rule
For missense variants, BP4 requires REVEL at or below 0.3.
Evidence considered
- REVEL score 0.301
- SpliceAI max delta 0.00
- BayesDel score -0.292277
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- variant consequence reviewed
- SpliceAI reviewed
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.301. BayesDel score = -0.292277.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 20301303 ↗Noonan Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20301557 ↗Noonan Syndrome with Multiple Lentigines.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20876176 ↗Noonan syndrome: clinical features, diagnosis, and management guidelines.Romano AA et al. · 2010No paper-specific finding is recorded.
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PMID 24728327 ↗Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.No paper-specific finding is recorded.
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PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Authors/Task Force members et al. · 2014No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
90 / 1,614,070 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
5 Benign · 2 Likely benign · 1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243113
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/135112/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112884118-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112446314-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/PTPN11/N18S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.53A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This 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 v2.1
This 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.
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.301. BayesDel score = -0.292277.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.