chr12-112450394-G-T
Variant summary
The NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000009, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.99). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002540265: "In vitro functional studies demonstrated that the p.Ala72Ser variant significantly increased PTPN11 phosphatase activity and prolonged ERK activation." PMID:15179047" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.A72G: Pathogenic/Likely_pathogenic (ClinVar VariationId 13325, 2 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 25 samples carry this exact amino acid change out of 150 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Noonan syndrome 1 (ns1); it is also listed as a COSMIC curated somatic variant.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
Publications
- LEOPARD syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
- metachondromatosisInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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Classification according to ACMG Germline Pathogenicity v2019
Our verdict: Pathogenic. The variant received 17 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| PS3Functional studies show damaging effect | Well-established functional study supports damaging effect (PS3); SCV002540265: "In vitro functional studies demonstrated that the p.Ala72Ser variant significantly increased PTPN11 phosphatase activity and prolonged ERK activation." PMID:15179047; SCV000659045: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 14974085, 16399795).; SCV000698070: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the variant increased phosphatase activity under basal and stimulated conditions (Tartaglia_2006, Bocchinfuso_2007).; SCV000057376: Published functional studies demonstrate a damaging effect; results in significantly increased tyrosine-phosphatase activity resulting in prolonged ligand-dependent ERK2 activation (Fragale et al., 2004; Oishi et al., 2006; Bocchinfuso et at., 2007); SCV000206725: Functional analyses demonstrate increased tyrosine-phosphatase activity resulting in prolonged ERK2 activation (Bocchinfuso 2007, Fragale 2004, Oishi 2006).; SCV006139677: "In COS-7 cells expressing this mutation, protein tyrosine phosphatase activities were increased 5-6 times compared to wild type and also induce a prolonged activation of ERK2 (Fragale, 2004)." | ||
| PM1Mutational hot spot or critical domain | Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 24 pathogenic, 0 benign (OR vs. background: 245.0). | ||
| PM2Absent/extremely low in population databases | Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate. | ||
| PM5Novel missense at known pathogenic residue | Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.A72G: Pathogenic/Likely_pathogenic (ClinVar VariationId 13325, 2 stars) | ||
| PP2Missense in gene with low missense rate | Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 4.953). ClinVar shows strong pathogenic missense enrichment: 163 P/LP and 22 B/LB missense entries (ratio 7.4×). | ||
| PP3Computational evidence supports damaging effect | Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate). | ||
| PP5Reputable source reports pathogenic | ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (19/19 total P/LP). |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
PTPN11 | MANE Select | c.214G>T p.Ala72Ser | missense | Exon 3 of 16 | Prot: NP_002825.3 | |
PTPN11 | c.214G>T p.Ala72Ser | missense | Exon 3 of 16 | Prot: NP_001317366.1 UniProt: | ||
PTPN11 | c.211G>T p.Ala71Ser | missense | Exon 3 of 16 | Prot: NP_001361554.1 |
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
PTPN11 | TSL:1MANE Select | c.214G>T p.Ala72Ser | missense | Exon 3 of 16 | Prot: ENSP00000340944.3 UniProt: | |
PTPN11 | TSL:5 | c.214G>T p.Ala72Ser | missense | Exon 3 of 15 | Prot: ENSP00000489597.1 UniProt: | |
PTPN11 | TSL:1 | c.214G>T p.Ala72Ser | missense | Exon 3 of 11 | Prot: ENSP00000376376.1 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 4 sources | |||||
GnomAD3 genomes | Cov:32 | ||||
GnomAD4 exome Warning | AF: 6.84e-7 | AC:1 | Hom:0 | AN:1461322 | Cov:31 |
GnomAD4 genome | Cov:32 | ||||
ALFA (dbGaP/dbSNP Allele Frequency Aggregator) | AF: 0.00000491 | AC:1 | Hom:0 | AN:203630 | |
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 29 | |
AlphaMissense | Pathogenic | 0.92 | |
BayesDel_addAF | Pathogenic | 0.44 | D |
BayesDel_noAF | Pathogenic | 0.40 | |
CADD | Pathogenic | 27 | |
CardioboostCm | Uncertain | 0.57 | |
DANN | Uncertain | 1.0 | |
DEOGEN2 | Pathogenic | 0.82 | D |
Eigen | Uncertain | 0.58 | |
Eigen_PC | Uncertain | 0.64 | |
FATHMM_MKL | Pathogenic | 0.99 | D |
GPN-Star LLR | N/A | -8.4 | |
GPN-Star score | N/A | 8.4 | |
LIST_S2 | Benign | 0.75 | T |
M_CAP | Uncertain | 0.26 | D |
MetaRNN | Pathogenic | 0.94 | D |
MetaSVM | Pathogenic | 0.96 | D |
Mutation Taster | N/A | 2/98 | disease causing (ClinVar) |
MutationAssessor | Benign | 0.66 | N |
PhyloP100 | Pathogenic | 10 | |
popEVE | Benign | -3.5 | |
PrimateAI | Pathogenic | 0.85 | D |
PROVEAN | Uncertain | -2.7 | D |
RBP_binding_hub_radar | N/A | 0.0 | |
RBP_regulation_power_radar | N/A | 1.7 | |
REVEL | Pathogenic | 0.81 | |
Sift | Uncertain | 0.0060 | D |
Sift4G | Benign | 0.081 | T |
Varity_R | N/A | 0.93 | |
VESM-3B | Benign | -5.3 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.0 | |
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.