Variant classification summary

NM_002830.4:c.872A>T

PTPN4 · NP_002821.1:p.(Tyr291Phe) · NM_002830.4

GRCh37: chr2:120677688 A>T · GRCh38: chr2:119920112 A>T

Gene: PTPN4 Transcript: NM_002830.4

Final call

VUS

PM2 supporting

Variant details

Gene

PTPN4

Transcript

NM_002830.4

Protein

NP_002821.1:p.(Tyr291Phe)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed allele frequency 0.

Final determination: Under generic ACMG/AMP 2015 rules, one supporting criterion alone satisfies no pathogenic, likely pathogenic, benign, or likely benign combination, so the result is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	PS1 could not be assessed because its agent did not produce valid output.
PS2	Not assessed	Not assessed: no proband-specific parental testing or family-history data establish confirmed maternity and paternity for a de novo variant.	PMID:25741868
PS3	Not assessed	Not assessed: no variant-specific functional assay with validated controls or reproducible damaging results was available for p.Tyr291Phe.	clinvar PMID:25741868
PS4	Not assessed	Not assessed: no case-control prevalence, odds ratio or relative risk, or confidence interval was available to evaluate the >5.0 PS4 requirement.
PM1	Not assessed	PM1 could not be assessed because its agent did not produce valid output.
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, giving observed frequency 0, below the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no pathogenic partner variant or parent/offspring testing establishes that PTPN4 c.872A>T is in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	PM5 could not be assessed because its agent did not produce valid output.
PM6	Not assessed	Not assessed: no proband-specific parental testing or clinical data support an assumed de novo occurrence without maternity and paternity confirmation.	PMID:25741868
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are available to demonstrate co-segregation of the variant with disease.	PMID:25741868
PP2	Not assessed	PP2 could not be assessed because its agent did not produce valid output.
PP3	Not met	Not met: REVEL 0.718 is below the PP3 moderate threshold of 0.773 and remains gray-zone rather than supporting PP3.	revel
PP4	Not assessed	Not assessed: no variant-case phenotype or family history was available to establish a highly specific single-etiology disease presentation.	clinvar
PP5	Not met	Not met: ClinVar reports exact-variant uncertain significance from one non-expert submission, not a pathogenic or likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, giving observed frequency 0, below the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: observed allele frequency was 0 in gnomAD v2.1 and v4.1, below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy-adult carrier or homozygote observation is available to evaluate the BS2 requirement.
BS3	Not assessed	Not assessed: no variant-specific functional assay with validated controls or reproducible normal-function results was available for p.Tyr291Phe.	clinvar PMID:25741868
BS4	Not assessed	Not assessed: no affected relatives with phenotype and genotype data are available to establish lack of segregation.	PMID:25741868
BP1	Not assessed	BP1 could not be assessed because its agent did not produce valid output.
BP2	Not assessed	Not assessed: no pathogenic partner variant or phase result demonstrates the cis/trans configuration required for BP2.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.718 exceeds the generic BP4 supporting threshold of 0.29, so computational evidence does not support a benign effect.	revel
BP5	Not assessed	Not assessed: no case evidence documented an alternate molecular basis for the disease alongside this variant.
BP6	Not met	Not met: ClinVar reports exact-variant uncertain significance from one non-expert submission, not a benign or likely benign expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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