NM_001330437.1:c.526-8C>A

PTPN11 · NP_001317366.1:p.? · NM_001330437.1

GRCh37: chr12:112892360 C>A · GRCh38: chr12:112454556 C>A

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting BP6 supporting benign

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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
PVS1	N/A	This 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.	cspec pvs1_variant_assessment
PS1	N/A	This 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.	cspec
PS2	Not assessed	No confirmed de novo observation with documented parental testing and phenotype information was identified for this variant.	cspec
PS3	Not assessed	No published RNA study, minigene assay, or other approved functional assay specific to this variant was identified.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Not assessed	Although this variant has been submitted to ClinVar, no case-count or enrichment data were identified to meet the RASopathy point-based PS4 thresholds.	clinvar cspec
PM1	N/A	PM1 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.	cspec
PM2	Not met	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.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	The PTPN11 RASopathy specification lists PM3 as not applicable.	cspec
PM4	N/A	This variant is not an in-frame insertion, in-frame deletion, or stop-loss variant.	cspec
PM5	N/A	The PTPN11 PM5 rule uses classic same-residue missense logic. This variant is not missense-like and no residue-based comparator analysis is applicable.	cspec pm5_candidates
PM6	Not assessed	No presumed de novo report without full parental confirmation was identified for this variant.	cspec
PP1	Not assessed	No segregation data were identified for this variant.	cspec
PP2	N/A	PP2 in this specification is a missense-based rule using gene-level missense constraint. This intronic splice-region variant is not a missense variant.	cspec
PP3	Not met	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.	spliceai cspec
PP4	N/A	The PTPN11 RASopathy specification lists PP4 as not applicable.	cspec
PP5	N/A	The PTPN11 RASopathy specification lists PP5 as not applicable.	cspec
BA1	Met	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.	gnomad_v2 gnomad_v4 cspec
BS1	Met	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.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No case-level evidence was identified showing this variant in unaffected individuals at the point threshold required by the RASopathy specification.	cspec
BS3	N/A	The PTPN11 RASopathy specification lists BS3 as not applicable.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant.	cspec
BP1	N/A	BP1 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.	cspec pvs1_variant_assessment
BP2	Not assessed	No phase data or alternate molecular explanation data were identified to support BP2 scoring.	cspec
BP3	N/A	The PTPN11 RASopathy specification lists BP3 as not applicable.	cspec
BP4	Met	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.	spliceai cspec
BP5	Not assessed	No independent molecular diagnosis or alternate cause data were identified to support BP5 scoring.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	Not assessed	This non-canonical intronic variant has a low SpliceAI score, but no conservation evidence was identified to confirm the full BP7 requirements.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.