Variant classification summary

NM_001330437.1:c.1662G>A

PTPN11 · NP_001317366.1:p.(Ala554=) · NM_001330437.1

GRCh37: chr12:112939998 G>A · GRCh38: chr12:112502194 G>A

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Likely Benign

BP4 supporting BS1 strong BP6 supporting benign

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Ala554=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

Final determination: Rule18 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PM5	N/A	This 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.	cspec
PS1	N/A	This 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.	cspec
PP3	Not met	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.	spliceai cspec
PM4	N/A	This variant is synonymous and does not change protein length, so PM4 does not apply.	cspec
PM2	Not met	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.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	No confirmed de novo occurrence with documented maternity and paternity confirmation was identified, so PS2 cannot be applied from the available evidence.	clinvar cspec
PVS1	N/A	This 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.	cspec pvs1_gene_context pvs1_variant_assessment
BP7	Not assessed	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.	spliceai cspec
PM1	Not met	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.	cspec hotspots
BP1	N/A	BP1 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.	cspec
BP4	Met	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.	spliceai cspec
BP3	N/A	BP3 is not applicable in this RASopathy VCEP framework.	cspec
PS3	Not assessed	No variant-specific approved functional study showing a damaging effect on protein function or splicing was identified, so PS3 was not applied.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM3	N/A	PM3 is not applicable in this RASopathy VCEP framework.	cspec
PP4	N/A	PP4 is not applicable in this RASopathy VCEP framework.	cspec
BS3	N/A	BS3 is not applicable in this RASopathy VCEP framework.	cspec
PP5	N/A	PP5 is not for use in this VCEP framework.	cspec
BP5	Not assessed	No alternative molecular diagnosis explaining the phenotype was identified, so BP5 could not be assessed from the available evidence.	cspec
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
PP2	N/A	PP2 in this framework is specified for missense variation, and this variant is synonymous.	cspec
BS4	Not assessed	No segregation study showing lack of segregation with disease was identified, so BS4 was not applied.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be applied.	clinvar cspec
BS1	Met	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.	gnomad_v2 gnomad_v4 cspec
BP2	Not assessed	No phase data or co-occurrence with another pathogenic variant were identified, so BP2 was not applied.	cspec
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of unaffected individuals for BS2, so BS2 was not applied.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified, so PM6 was not applied.	clinvar cspec
PS4	Not assessed	No case-control enrichment or exact affected-case count meeting the RASopathy VCEP point-based PS4 thresholds was identified, so PS4 was not applied.	clinvar cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar

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