About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.1662G>A, p.(Ala554=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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
BS1Strong
BS1 · strong
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.
BP4Supporting
BP4 · supporting
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.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Likely 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 Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BP4 supporting, BS1 strong, BP6 supporting benign; maps to Likely 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
46 / 1,613,744 alleles
gnomAD v4.1: 46 / 1,613,744 alleles. Recorded AF 2.85051e-05. Recorded homozygote count 0.
gnomAD 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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 4 not met · 10 not assessed · 11 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 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.
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.
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.
No criteria match.
Met · 3
BS1 StrongThis 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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥ 0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00067298 (0.067298%).
- gnomAD v4.1 grpmax FAF 0.00043105 (0.043105%).
Sources
BP4 SupportingAvailable 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. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.04
- DS_AL 0.18
- DS_DG 0.00
- DS_DL 0.12
- max delta 0.18.
- Variant is synonymous p.(Ala554=).
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available evidence does not place this variant in a PTPN11 critical residue or established hotspot used for PM1. Codon 554 is not included among the VCEP-listed directly interacting residues, and no statistically significant hotspot evidence was identified for Ala554. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table.
Evidence considered
- PTPN11 PM1 residues listed by the VCEP do not include Ala554.
- Cancer Hotspots review found no residue row and no statistically significant hotspot for A554.
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at total AF 0.01394% with grpmax FAF 0.067298% and in gnomAD v4.1 at total AF 0.00285% with grpmax FAF 0.043105%, so PM2 is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.000139413
- grpmax FAF 0.00067298.
- gnomAD v4.1 total AF 0.0000285051
- grpmax FAF 0.00043105.
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL and BayesDel scores were not available, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.18, which does not support a pathogenic splicing effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL not found for this variant.
- BayesDel not found for this variant.
- SpliceAI DS_AG 0.04
- DS_AL 0.18
- DS_DG 0.00
- DS_DL 0.12
- max delta 0.18.
Sources
BA1 The stand-alone benign threshold was not met consistently across the available gnomAD datasets. Although gnomAD v2.1 shows grpmax FAF 0.067298%, gnomAD v4.1 shows grpmax FAF 0.043105%, which is below the BA1 threshold of 0.05%, so BA1 was not applied. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥ 0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00067298 (0.067298%).
- gnomAD v4.1 grpmax FAF 0.00043105 (0.043105%).
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Point-based de novo scoring per RASopathy VCEP specifications.
Evidence considered
- Exploratory review did not identify a confirmed de novo report for this exact variant.
- ClinVar summary does not provide confirmed de novo evidence.
Still missing
- Case-level de novo reports with parental confirmation were not identified.
Sources
PS3 No variant-specific approved functional study showing a damaging effect on protein function or splicing was identified, so PS3 was not applied. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- RASopathy VCEP lists approved assay types for PTPN11 functional assessment.
- No assay result for this exact variant was identified in the reviewed materials.
Still missing
- No variant-specific approved functional assay result was identified for p.(Ala554=).
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
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. Details ▾Hide ▴
Rule
Supporting at ≥1 point; Moderate at ≥3 points; Strong at ≥5 points.
Evidence considered
- ClinVar reports benign and likely benign assertions
- but no PS4-qualifying case count was documented in the reviewed evidence.
- Exploratory review did not identify case-enrichment data for this exact variant.
Still missing
- No exact affected-case counts or formal enrichment data were identified for this variant.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not applied. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals for BS2, so BS2 was not applied. Details ▾Hide ▴
Rule
Point-based benign evidence from observation in unaffected individuals.
Evidence considered
- Population frequency data were available
- but no BS2-specific unaffected carrier evidence was identified.
Still missing
- No unaffected adult carrier dataset or case-level unaffected carrier evidence was identified.
Sources
BS4 No segregation study showing lack of segregation with disease was identified, so BS4 was not applied. Details ▾Hide ▴
BP2 No phase data or co-occurrence with another pathogenic variant were identified, so BP2 was not applied. Details ▾Hide ▴
Rule
Point-based benign evidence for phase/co-occurrence context.
Evidence considered
- No co-occurrence or phase information was identified for this case.
Still missing
- No in trans or in cis phase evidence was identified.
Sources
BP5 No alternative molecular diagnosis explaining the phenotype was identified, so BP5 could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Points awarded for an alternative molecular cause of a RASopathy in a different gene or a phenotype fully explained by a different causative variant.
Evidence considered
- No alternate molecular diagnosis data were provided for this case.
Still missing
- No case-level alternative molecular explanation was identified.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.18. However, the available evidence did not establish whether the altered nucleotide is not highly conserved, so the full BP7 rule was not completed. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Synonymous variant p.(Ala554=).
- SpliceAI max delta score 0.18 predicts no significant splice impact.
Still missing
- No conservation evidence was identified for the altered nucleotide.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is synonymous and does not fall into a null-variant category. The variant-level PVS1 assessment states that it is not a nonsense, frameshift, or canonical ±1/2 splice variant, so PVS1 is not applicable. Details ▾Hide ▴
Rule
PVS1 is not applicable in this RASopathy framework for this variant type.
Evidence considered
- Variant predicts p.(Ala554=).
- PVS1 variant assessment: apply_generic_pvs1_framework=false
- variant bucket=other.
Sources
PS1 N/AThis variant does not produce an amino acid substitution, so it cannot meet PS1, which requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- PTPN11 RASopathy VCEP PS1 requires the same amino acid substitution as an established pathogenic variant.
- NM_001330437.1:c.1662G>A predicts p.(Ala554=)
- with no amino acid change.
Sources
PM3 N/APM3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 criteria specification marks PM3 as not applicable.
Sources
PM4 N/AThis variant is synonymous and does not change protein length, so PM4 does not apply. Details ▾Hide ▴
Rule
No known repetitive areas in gene. Use as described.
Evidence considered
- NM_001330437.1:c.1662G>A predicts p.(Ala554=).
- PM4 is specified for in-frame protein length changes or stop-loss variants.
Sources
PM5 N/AThis is a synonymous variant and does not create a novel missense change at a codon with a previously established pathogenic missense variant, so PM5 does not apply. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon.
Evidence considered
- PTPN11 RASopathy VCEP PM5 is specified for missense changes at the same codon.
- NM_001330437.1:c.1662G>A predicts p.(Ala554=)
- with no amino acid substitution.
Sources
PP2 N/APP2 in this framework is specified for missense variation, and this variant is synonymous. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- Variant predicts p.(Ala554=).
- PTPN11 PP2 specification is for missense variants.
Sources
PP4 N/APP4 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 criteria specification marks PP4 as not applicable.
Sources
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- PTPN11 criteria specification marks PP5 as not applicable.
Sources
BS3 N/ABS3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 criteria specification marks BS3 as not applicable.
Sources
BP1 N/ABP1 in this framework is reserved for truncating loss-of-function variants in a gene primarily associated with gain-of-function disease, and this variant is not truncating. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Variant is synonymous
- not truncating.
- RASopathy VCEP BP1 specification is for truncating variants in this context.
Sources
BP3 N/ABP3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 criteria specification marks BP3 as not applicable.
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.1662G>A
- Protein (HGVS p.)
- NP_001317366.1:p.(Ala554=)
- GRCh38
- chr12:112502194 G>A
- GRCh37
- chr12:112939998 G>A
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
46 / 1,613,744 alleles
AF 2.85e-05 · 0 homozygotes · FAF 0.000431
gnomAD v2.1
35 / 251,052 alleles
AF 0.000139 · 0 homozygotes · FAF 0.000673
By genetic ancestry
gnomAD v4.1
AF 2.9e-05 · 46 / 1,613,744 alleles · 0 hom · FAF 0.00043
| Admixed American35 / 59,988 | 0.00058 |
| Remaining individuals2 / 62,468 | 3.2e-05 |
| East Asian1 / 44,894 | 2.2e-05 |
| South Asian1 / 91,070 | 1.1e-05 |
| European (non-Finnish)7 / 1,179,846 | 5.9e-06 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00014 · 35 / 251,052 alleles · 0 hom · FAF 0.00067
| Admixed American32 / 34,590 | 0.00093 |
| East Asian2 / 18,392 | 0.00011 |
| European (non-Finnish)1 / 113,360 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingAvailable 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. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.04
- DS_AL 0.18
- DS_DG 0.00
- DS_DL 0.12
- max delta 0.18.
- Variant is synonymous p.(Ala554=).
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL and BayesDel scores were not available, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.18, which does not support a pathogenic splicing effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL not found for this variant.
- BayesDel not found for this variant.
- SpliceAI DS_AG 0.04
- DS_AL 0.18
- DS_DG 0.00
- DS_DL 0.12
- max delta 0.18.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.18. However, the available evidence did not establish whether the altered nucleotide is not highly conserved, so the full BP7 rule was not completed. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Synonymous variant p.(Ala554=).
- SpliceAI max delta score 0.18 predicts no significant splice impact.
Still missing
- No conservation evidence was identified for the altered nucleotide.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
46 / 1,613,744 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/138843/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112939998-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112502194-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/A554=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.1662G%3EA
- 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= 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.
gnomAD 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.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.