About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.526-8C>A, p.?
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: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
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.
BS1Strong
BS1 · strong
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.
BP4Supporting
BP4 · supporting
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.
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, BP4 supporting, 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
2,078 / 1,595,796 alleles
gnomAD v4.1: 2,078 / 1,595,796 alleles. Recorded AF 0.00130217. Recorded homozygote count 4.
gnomAD 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.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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: 4 met · 2 not met · 10 not assessed · 12 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.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.
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%.
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.
No criteria match.
Met · 4
BA1 Stand aloneThis 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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 total AF 0.06730%
- gnomAD v4.1 total AF 0.13022%
Sources
BS1 StrongThis 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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 total AF 0.06730%
- gnomAD v4.1 total AF 0.13022%
Sources
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06
- DS_AG 0.06
- DS_AL 0.00
- DS_DG 0.00
- DS_DL 0.00
Sources
Not met · 2 · evaluated, threshold not reached
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.06730% (190/282310) and in gnomAD v4.1 at AF 0.13022% (2078/1595796), so the PTPN11 PM2 requirement is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires the variant to be absent from gnomAD.
Evidence considered
- gnomAD v2.1 total AF 0.000673019
- gnomAD v4.1 total AF 0.001302171
Sources
PP3 Available computational evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, which does not support PP3 for a splice-region variant. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.06
- SpliceAI max delta score 0.06
- No REVEL or BayesDel score available for this non-missense variant
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo observation with documented parental testing and phenotype information was identified for this variant. Details ▾Hide ▴
Rule
Apply point-based de novo scoring per the RASopathy specification.
Evidence considered
- No de novo evidence identified in the reviewed materials
Still missing
- No confirmed maternity and paternity data were identified for this variant.
- No case-specific phenotype documentation supporting PS2 point assignment was identified.
Sources
PS3 No published RNA study, minigene assay, or other approved functional assay specific to this variant was identified. Details ▾Hide ▴
Rule
Supporting with one approved assay; Moderate with two or more different approved assays.
Evidence considered
- No exact-variant functional assay evidence identified
Still missing
- No exact-variant splicing assay result was identified.
- No approved functional study for this variant was identified in the reviewed VCEP materials.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
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. Details ▾Hide ▴
Rule
Apply point-based prevalence scoring in affected individuals under the RASopathy specification.
Evidence considered
- ClinVar contains this variant
- No PS4 point-based evidence identified
Still missing
- No affected proband count was identified for PS4 scoring.
- No case-control or enrichment dataset was identified for this variant.
Sources
PM6 No presumed de novo report without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Apply point-based de novo scoring for assumed de novo observations per the RASopathy specification.
Evidence considered
- No PM6 evidence identified
Still missing
- No presumed de novo case report was identified.
- No phenotype-specific point assignment evidence was identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Supporting at ≥3 informative meioses, Moderate at ≥5, Strong at ≥7.
Evidence considered
- No segregation evidence identified
Still missing
- No informative meioses were identified.
- No family-based cosegregation report was identified.
Sources
BS2 No case-level evidence was identified showing this variant in unaffected individuals at the point threshold required by the RASopathy specification. Details ▾Hide ▴
Rule
Apply point-based scoring for observations in unaffected individuals per the RASopathy specification.
Evidence considered
- No BS2-specific unaffected carrier dataset identified
Still missing
- No phenotype-vetted unaffected carrier data were identified for BS2 point scoring.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
Requires one informative meiosis under the PTPN11 specification.
Evidence considered
- No BS4 evidence identified
Still missing
- No informative family data showing lack of segregation were identified.
Sources
BP2 No phase data or alternate molecular explanation data were identified to support BP2 scoring. Details ▾Hide ▴
Rule
Apply point-based scoring per the RASopathy specification.
Evidence considered
- No BP2 evidence identified
Still missing
- No cis/trans phase evidence was identified.
- No BP2 point-based evidence was identified.
Sources
BP5 No independent molecular diagnosis or alternate cause data were identified to support BP5 scoring. Details ▾Hide ▴
Rule
Apply point-based scoring per the RASopathy specification.
Evidence considered
- No BP5 evidence identified
Still missing
- No BP5 point-based evidence was identified.
Sources
BP7 This non-canonical intronic variant has a low SpliceAI score, but no conservation evidence was identified to confirm the full BP7 requirements. Details ▾Hide ▴
Rule
Applicable to intronic positions except canonical splice sites when splicing algorithms predict no impact and the nucleotide is not highly conserved; use with BP4.
Evidence considered
- SpliceAI max delta score 0.06
- Variant is intronic and outside canonical splice positions
Still missing
- No nucleotide conservation evidence was identified for this position.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis non-canonical intronic variant is outside the default null-variant categories, and the PTPN11 RASopathy specification indicates that PVS1 is not used for this disease framework. Details ▾Hide ▴
Rule
PVS1 not applicable in the PTPN11 RASopathy specification; generic PVS1 scaffold does not place this variant in a default null-variant bucket.
Evidence considered
- NM_001330437.1:c.526-8C>A is intronic at c.526-8
- Variant is not at a canonical ±1/2 splice position
- PTPN11 RASopathy VCEP marks PVS1 as not applicable
Sources
cspec ↗pvs1_variant_assessment
PS1 N/AThis criterion applies to the same amino acid change as an established pathogenic variant. No amino acid substitution is defined for this intronic splice-region variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- Protein consequence is NP_001317366.1:p.?
- Variant is not missense-like
Sources
PM1 N/APM1 in the PTPN11 specification is limited to defined critical protein residues and domains. This intronic splice-region variant does not map to those missense-domain rules. Details ▾Hide ▴
Rule
Applicable only to specified critical and well-established functional domain residues in PTPN11.
Evidence considered
- Variant is intronic and has no defined amino acid residue change
Sources
PM3 N/AThe PTPN11 RASopathy specification lists PM3 as not applicable. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PM3 marked not applicable in the PTPN11 specification
Sources
PM4 N/AThis variant is not an in-frame insertion, in-frame deletion, or stop-loss variant. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is intronic
Sources
PM5 N/AThe PTPN11 PM5 rule uses classic same-residue missense logic. This variant is not missense-like and no residue-based comparator analysis is applicable. Details ▾Hide ▴
Rule
Classic same-residue missense PM5 logic in PTPN11.
Evidence considered
- Protein consequence is p.?
- PM5 candidate review found the variant was not eligible for classic same-residue missense PM5
Sources
cspec ↗pm5_candidates
PP2 N/APP2 in this specification is a missense-based rule using gene-level missense constraint. This intronic splice-region variant is not a missense variant. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- Variant is intronic and not missense
Sources
PP4 N/AThe PTPN11 RASopathy specification lists PP4 as not applicable. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PP4 marked not applicable in the PTPN11 specification
Sources
PP5 N/AThe PTPN11 RASopathy specification lists PP5 as not applicable. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PP5 marked not applicable in the PTPN11 specification
Sources
BS3 N/AThe PTPN11 RASopathy specification lists BS3 as not applicable. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- BS3 marked not applicable in the PTPN11 specification
Sources
BP1 N/ABP1 in the PTPN11 RASopathy specification is intended for truncating or other loss-of-function variants in the relevant context. This non-canonical intronic variant is not established as a truncating loss-of-function allele. Details ▾Hide ▴
Rule
Use BP1 for truncating/LOF variants in the specified RASopathy context.
Evidence considered
- Variant is intronic at c.526-8
- Generic PVS1 scaffold does not classify this variant in a default null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
BP3 N/AThe PTPN11 RASopathy specification lists BP3 as not applicable. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- BP3 marked not applicable in the PTPN11 specification
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.526-8C>A
- Protein (HGVS p.)
- NP_001317366.1:p.?
- GRCh38
- chr12:112454556 C>A
- GRCh37
- chr12:112892360 C>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
2,078 / 1,595,796 alleles
AF 0.0013 · 4 homozygotes · FAF 0.00164
gnomAD v2.1
190 / 282,310 alleles
AF 0.000673 · 1 homozygotes · FAF 0.00112
By genetic ancestry
gnomAD v4.1
AF 0.0013 · 2078 / 1,595,796 alleles · 4 hom · FAF 0.0016
| European (non-Finnish)1980 / 1,164,018 | 0.00172 hom |
| Remaining individuals57 / 61,836 | 0.000921 hom |
| African/African American25 / 74,664 | 0.00033 |
| Admixed American9 / 59,958 | 0.00015 |
| European (Finnish)7 / 64,016 | 0.000111 hom |
0 alternate alleles recorded in 5 other groups: Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00067 · 190 / 282,310 alleles · 1 hom · FAF 0.0011
| European (non-Finnish)167 / 128,656 | 0.0013 |
| Remaining individuals5 / 7,208 | 0.00069 |
| African/African American7 / 24,968 | 0.00028 |
| Admixed American8 / 35,434 | 0.00023 |
| European (Finnish)3 / 25,122 | 0.000121 hom |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, South Asian.
Statements
gnomAD 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.
gnomAD 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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational 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. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06
- DS_AG 0.06
- DS_AL 0.00
- DS_DG 0.00
- DS_DL 0.00
Sources
PP3 Available computational evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, which does not support PP3 for a splice-region variant. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.06
- SpliceAI max delta score 0.06
- No REVEL or BayesDel score available for this non-missense variant
Sources
BP7 This non-canonical intronic variant has a low SpliceAI score, but no conservation evidence was identified to confirm the full BP7 requirements. Details ▾Hide ▴
Rule
Applicable to intronic positions except canonical splice sites when splicing algorithms predict no impact and the nucleotide is not highly conserved; use with BP4.
Evidence considered
- SpliceAI max delta score 0.06
- Variant is intronic and outside canonical splice positions
Still missing
- No nucleotide conservation evidence was identified for this position.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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
2,078 / 1,595,796 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 ↗
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/36709/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112892360-C-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112454556-C-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.5…
- OncoKB ↗www.oncokb.org/gene/PTPN11/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=187365121
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= 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.
gnomAD 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.
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV105261528, n = 1 times).