About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.1221A>G, p.(Gly407=)
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 exceeds the PTPN11 RASopathy BA1 filtering allele frequency threshold of 0.05%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold.
BS1Strong
BS1 · strong
This variant exceeds the PTPN11 RASopathy BS1 filtering allele frequency threshold of 0.025%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BS1 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, 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
147 / 1,613,208 alleles
gnomAD v4.1: 147 / 1,613,208 alleles. Recorded AF 9.11228e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000186931; MAF= 0.01869%, 47/251430 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00147001; MAF= 0.14700%, 45/30612 alleles, homozygotes = 0); grpmax FAF= 0.00112836.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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 · 5 not met · 11 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.1221A>G (p.Gly407=) variant has not been identified in a statistically significant somatic hotspot and has been reported in ClinVar as Benign, including a benign expert-panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.
In gnomAD, this variant exceeds the PTPN11 RASopathy benign population thresholds, with grpmax filtering allele frequencies of 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold of 0.05% and the BS1 threshold of 0.025%.
This synonymous variant does not change the encoded amino acid, and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02.
No criteria match.
Met · 3
BA1 Stand aloneThis variant exceeds the PTPN11 RASopathy BA1 filtering allele frequency threshold of 0.05%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥ 0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.11284%
- gnomAD v4.1 grpmax FAF 0.13502%
- BA1 threshold 0.05000%
Sources
BS1 StrongThis variant exceeds the PTPN11 RASopathy BS1 filtering allele frequency threshold of 0.025%. The gnomAD grpmax filtering allele frequency is 0.11284% in v2.1 and 0.13502% in v4.1, both above the BS1 threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥ 0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.11284%
- gnomAD v4.1 grpmax FAF 0.13502%
- BS1 threshold 0.02500%
Sources
Not met · 5 · evaluated, threshold not reached
PS1 This variant does not change the encoded amino acid, so it does not match a previously established pathogenic amino acid substitution. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- PTPN11 c.1221A>G is NP_001317366.1:p.(Gly407=)
- PTPN11 VCEP PS1 requires the same amino acid change as a previously established pathogenic variant
Sources
PM1 Codon 407 is not among the PTPN11 RASopathy VCEP PM1 residues, and available hotspot review did not identify a statistically significant hotspot at G407, so PM1 is not met. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]).
Evidence considered
- PTPN11 VCEP PM1 residue list does not include codon 407
- Cancer Hotspots review reported no statistically significant hotspot at G407
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 0.01869% overall and in gnomAD v4.1 at 0.00911% overall, so the PM2 absence criterion is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.01869% (47/251430)
- gnomAD v4.1 total AF 0.00911% (147/1613208)
Sources
PM5 This synonymous variant does not create an amino acid substitution at codon 407, so it does not meet the PTPN11 same-codon missense rule. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon.
Evidence considered
- PTPN11 c.1221A>G is NP_001317366.1:p.(Gly407=)
- PTPN11 VCEP PM5 applies to different pathogenic missense changes at the same codon
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.02
- Variant is synonymous: p.(Gly407=)
Sources
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo occurrence with phenotype and parental relationship data was identified in the available sources, so the PS2 point-based de novo criterion could not be assessed. Details ▾Hide ▴
Rule
PS2 is applied using the RASopathy de novo point system.
Evidence considered
- Available ClinVar record shows a benign expert panel assertion but no de novo evidence details in the retrieved materials
- PTPN11 VCEP PS2 uses a point-based de novo framework
Still missing
- Variant-specific de novo case reports
- Parental testing details
- Phenotype confirmation for any proband
Sources
PS3 No approved functional assay result specific to this synonymous variant was identified in the available RASopathy VCEP functional study materials, so PS3 was not assessed. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- RASopathy VCEP approved functional studies file was reviewed
- No variant-specific assay evidence for p.(Gly407=) was identified in the retrieved materials
Still missing
- Variant-specific approved functional assay data
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
PS4 The available sources did not provide deduplicated affected proband counts or case-control enrichment data for this exact variant, so the PTPN11 PS4 point-based criterion could not be assessed. Details ▾Hide ▴
Rule
Strong ≥5 points; Moderate ≥3 points; Supporting ≥1 point.
Evidence considered
- ClinVar shows a benign expert panel assertion but the retrieved materials did not include countable PS4 proband evidence
- PTPN11 VCEP PS4 uses a point-based affected-case framework
Still missing
- Independent affected proband counts
- Case-control enrichment data
Sources
PM6 No assumed de novo report with sufficient variant-specific family detail was identified, so PM6 could not be assessed. Details ▾Hide ▴
Rule
Strong = 2 points; Moderate = 1 point; Supporting = 0.5 point.
Evidence considered
- No PM6-relevant parental-testing wording was identified in the retrieved materials
- PTPN11 VCEP PM6 uses a point-based de novo framework
Still missing
- Variant-specific de novo reports without full parentage confirmation
Sources
PP1 No segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals, so BS2 was not assessed. Population frequency evidence was instead captured under BA1 and BS1. Details ▾Hide ▴
Rule
Strong = -4 points; Supporting = -1 point.
Evidence considered
- Population frequency is high in gnomAD but unaffected clinical phenotype data were not provided
- PTPN11 VCEP BS2 uses a point-based framework
Still missing
- Well-phenotyped unaffected carrier data
Sources
BS4 No family data showing lack of segregation were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
BP2 No phase data were identified showing this variant with another pathogenic variant in cis or trans, so BP2 was not assessed. Details ▾Hide ▴
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. However, the PTPN11 VCEP BP4 specification is calibrated for missense variants using REVEL 0.3 or lower, and no REVEL score is available for this synonymous change, so BP4 was not assessed under the gene-specific rule. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤ 0.3.
Evidence considered
- SpliceAI max delta score 0.02
- No REVEL score available for this synonymous variant
Still missing
- A gene-specific benign computational rule for synonymous variants
Sources
BP5 No evidence was identified showing that this variant occurs in a case with a fully alternate molecular explanation sufficient for the RASopathy BP5 point system, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 is applied using the RASopathy phenotype/alternate-cause point system.
Evidence considered
- No BP5-relevant alternate molecular explanation was documented in the retrieved variant-specific sources
- PTPN11 VCEP BP5 uses a point-based framework
Still missing
- Case-level phenotype and alternate-cause data
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. However, no nucleotide conservation evidence was identified in the available materials to satisfy the full BP7 rule, so BP7 was not assessed. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- Variant is synonymous p.(Gly407=)
- SpliceAI max delta score 0.02
Still missing
- Nucleotide conservation evidence for the altered base
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is not a nonsense, frameshift, canonical splice, or other null variant. The variant-level PVS1 assessment states that it does not fall into the generic PVS1 null-variant buckets, and the PTPN11 VCEP marks PVS1 as not applicable here. Details ▾Hide ▴
Rule
Not Applicable
Evidence considered
- Variant is synonymous p.(Gly407=)
- Variant-level PVS1 assessment says generic PVS1 framework does not apply
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
PM4 N/AThis variant is a synonymous substitution and does not cause a protein length change, in-frame insertion/deletion, or stop-loss effect. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- PTPN11 c.1221A>G is synonymous p.(Gly407=)
- PTPN11 VCEP PM4 is for protein length changes
Sources
PP2 N/APP2 in the PTPN11 RASopathy framework is a missense-based criterion, and this variant is synonymous. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- Variant is synonymous p.(Gly407=)
- PTPN11 VCEP PP2 is based on missense constraint
Sources
PP4 N/APP4 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PTPN11 RASopathy specification and was not used. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
BP1 N/ABP1 in the PTPN11 RASopathy framework is intended for truncating variants in genes without an established loss-of-function disease mechanism. This variant is synonymous and does not truncate the protein. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Variant is synonymous p.(Gly407=)
- PTPN11 VCEP BP1 is restricted to truncating variants
Sources
BP3 N/ABP3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.1221A>G
- Protein (HGVS p.)
- NP_001317366.1:p.(Gly407=)
- GRCh38
- chr12:112482202 A>G
- GRCh37
- chr12:112920006 A>G
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
147 / 1,613,208 alleles
AF 9.11e-05 · 0 homozygotes · FAF 0.00135
gnomAD v2.1
47 / 251,430 alleles
AF 0.000187 · 0 homozygotes · FAF 0.00113
By genetic ancestry
gnomAD v4.1
AF 9.1e-05 · 147 / 1,613,208 alleles · 0 hom · FAF 0.0014
| South Asian142 / 91,058 | 0.0016 |
| Remaining individuals4 / 62,448 | 6.4e-05 |
| European (non-Finnish)1 / 1,179,334 | 8.5e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.00019 · 47 / 251,430 alleles · 0 hom · FAF 0.0011
| South Asian45 / 30,612 | 0.0015 |
| Remaining individuals1 / 6,136 | 0.00016 |
| Admixed American1 / 34,592 | 2.9e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.11228e-05; MAF= 0.00911%, 147/1613208 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00155945; MAF= 0.15594%, 142/91058 alleles, homozygotes = 0); grpmax FAF= 0.00135023.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000186931; MAF= 0.01869%, 47/251430 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00147001; MAF= 0.14700%, 45/30612 alleles, homozygotes = 0); grpmax FAF= 0.00112836.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.02. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.02
- Variant is synonymous: p.(Gly407=)
Sources
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. However, the PTPN11 VCEP BP4 specification is calibrated for missense variants using REVEL 0.3 or lower, and no REVEL score is available for this synonymous change, so BP4 was not assessed under the gene-specific rule. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤ 0.3.
Evidence considered
- SpliceAI max delta score 0.02
- No REVEL score available for this synonymous variant
Still missing
- A gene-specific benign computational rule for synonymous variants
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. However, no nucleotide conservation evidence was identified in the available materials to satisfy the full BP7 rule, so BP7 was not assessed. Details ▾Hide ▴
Rule
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- Variant is synonymous p.(Gly407=)
- SpliceAI max delta score 0.02
Still missing
- Nucleotide conservation evidence for the altered base
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
147 / 1,613,208 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/436446/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112920006-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112482202-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/G407=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.1221A%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= 9.11228e-05; MAF= 0.00911%, 147/1613208 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00155945; MAF= 0.15594%, 142/91058 alleles, homozygotes = 0); grpmax FAF= 0.00135023.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000186931; MAF= 0.01869%, 47/251430 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00147001; MAF= 0.14700%, 45/30612 alleles, homozygotes = 0); grpmax FAF= 0.00112836.
ClinVar
This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Uncertain significance (1 clinical laboratory) 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 = 0.02).
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.