Variant classification summary

NM_001330437.1:c.1221A>G

PTPN11 · NP_001317366.1:p.(Gly407=) · NM_001330437.1

GRCh37: chr12:112920006 A>G · GRCh38: chr12:112482202 A>G

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Benign

BA1 stand-alone benign BS1 strong BP6 supporting benign

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Gly407=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

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.

Final determination: Rule17 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 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	Not met	This synonymous variant does not create an amino acid substitution at codon 407, so it does not meet the PTPN11 same-codon missense rule.	cspec
PS1	Not met	This variant does not change the encoded amino acid, so it does not match a previously established pathogenic amino acid substitution.	cspec
PP3	Not met	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.	spliceai cspec
PM4	N/A	This variant is a synonymous substitution and does not cause a protein length change, in-frame insertion/deletion, or stop-loss effect.	cspec
PM2	Not met	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.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	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.	clinvar cspec
PVS1	N/A	This 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.	cspec pvs1_variant_assessment
BP7	Not assessed	This is a synonymous variant and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02. However, no nucleotide conservation evidence was identified in the available materials to satisfy the full BP7 rule, so BP7 was not assessed.	spliceai cspec
PM1	Not met	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.	cspec hotspots
BP1	N/A	BP1 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.	cspec
BP4	Not assessed	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.	spliceai cspec
BP3	N/A	BP3 is not applicable in the PTPN11 RASopathy specification.	cspec
PS3	Not assessed	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.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PM3	N/A	PM3 is not applicable in the PTPN11 RASopathy specification.	cspec
PP4	N/A	PP4 is not applicable in the PTPN11 RASopathy specification.	cspec
BS3	N/A	BS3 is not applicable in the PTPN11 RASopathy specification.	cspec
PP5	N/A	PP5 is not applicable in the PTPN11 RASopathy specification and was not used.	cspec
BP5	Not assessed	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.	clinvar cspec
BA1	Met	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.	gnomad_v2 gnomad_v4 cspec
PP2	N/A	PP2 in the PTPN11 RASopathy framework is a missense-based criterion, and this variant is synonymous.	cspec
BS4	Not assessed	No family data showing lack of segregation were identified for this variant, so BS4 could not be assessed.	clinvar cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.	clinvar cspec
BS1	Met	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.	gnomad_v2 gnomad_v4 cspec
BP2	Not assessed	No phase data were identified showing this variant with another pathogenic variant in cis or trans, so BP2 was not assessed.	clinvar cspec
BS2	Not assessed	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.	gnomad_v2 gnomad_v4 cspec
PM6	Not assessed	No assumed de novo report with sufficient variant-specific family detail was identified, so PM6 could not be assessed.	clinvar cspec
PS4	Not assessed	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.	clinvar cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar

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