The PTPN4 NM_002830.4:c.872A>T (NP_002821.1:p.(Tyr291Phe)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PTPN4 encodes a protein tyrosine phosphatase that helps regulate cell signaling, including processes involved in cell growth, differentiation, and cell division. It interacts with glutamate receptors and may help transmit their signals by removing phosphate groups from proteins. PTPN4 has been studied in relation to cellular signaling, but no established disease association or specific role in cancer is described here.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 supporting is the only met criterion and does not satisfy any generic ACMG/AMP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.718. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers PTPN4, so the generic ACMG/AMP rules supplied for this case govern.
The available evidence supports neither phenotype-specific PP4 nor case-control PS4, and provides no alternate molecular basis for BP5.
The exact-variant ClinVar record is uncertain significance from a single non-expert submission; it cannot trigger PP5 or BP6.
Generic ACMG/AMP rules apply because no VCEP covers PTPN4.
The variant is missense, so PP3/BP4 are adjudicated from REVEL only; SpliceAI and BayesDel are not counted.
REVEL 0.718 is below PP3 moderate 0.773 and above BP4 supporting 0.29; neither criterion is met.
No criteria match.
PM2 is met at supporting strength. NM_002830.4:c.872A>T (NP_002821.1:p.(Tyr291Phe)) was absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 datasets. Its observed allele frequency was therefore 0, satisfying the supplied generic PM2 supporting threshold of <= 0.0001. The variant is a missense substitution rather than an indel, so the ACMG/AMP indel-calling caveat does not limit this assessment.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
This is a missense variant, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot be substituted. REVEL is 0.718, below the generic PP3 moderate threshold of >= 0.773 and above the supporting threshold of >= 0.644, so the result is indeterminate/gray-zone for PP3 and does not meet the criterion. BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... An indeterminate result on the applicable path means PP3/BP4 are simply not met.
PP5 is not met because the exact variant NM_002830.4:c.872A>T is classified in ClinVar as Uncertain significance by one single-submitter clinical laboratory, with no expert-panel submission; there is no reputable source reporting this exact variant as pathogenic or likely pathogenic. The governing rule is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation."
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The variant was absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency was 0 in both datasets and did not reach the generic stand-alone benign threshold of >= 0.05. No VCEP-specific population source rule applies; the generic all-comers datasets are therefore the applicable default. The variant is a single-nucleotide substitution, so the ACMG/AMP indel calling caveat does not apply.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met under the supplied generic calibration. The variant was absent from gnomAD v2.1 and gnomAD v4.1, with observed allele frequency 0, below the generic BS1 threshold of >= 0.01. No VCEP-specific disease-prevalence or ancestry threshold is available, and the population data do not show an allele frequency greater than expected for the disorder.
Allele frequency is greater than expected for disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
This is a missense variant, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot be substituted. REVEL is 0.718, above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... An indeterminate result on the applicable path means PP3/BP4 are simply not met.
BP6 is not met because the exact variant NM_002830.4:c.872A>T is classified in ClinVar as Uncertain significance by one single-submitter clinical laboratory, with no expert-panel submission; there is no reputable source reporting this exact variant as benign or likely benign. The governing rule is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation."
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No proband-specific clinical report or parental testing data were identified, so de novo status, maternity, paternity, disease phenotype, and family-history requirements cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
NM_002830.4:c.872A>T (NP_002821.1:p.(Tyr291Phe)) has no documented variant-specific, well-established in vitro or in vivo functional assay in the reviewed evidence. The only retrieved publication, PMID:25741868, is a general ACMG/AMP guideline and explicitly does not mention PTPN4 or this variant. The single-submitter ClinVar record contains a pre-assigned PS3 signal, but provides no assay method, controls, biological endpoint, reproducibility data, or result that can independently establish PS3. Therefore, PS3 cannot be assessed from the available functional evidence.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
No case-control study, affected-individual prevalence, control prevalence, odds ratio, relative risk, or confidence interval for NM_002830.4:c.872A>T was available. Therefore the PS4 threshold cannot be evaluated. The governing rule is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0."
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 cannot be assessed because the available evidence does not establish a recessive disorder for PTPN4, does not identify a pathogenic allele in the same individual, and provides no parent or offspring testing to establish trans phase for NM_002830.4:c.872A>T (p.Tyr291Phe).
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
No proband-specific clinical report or parental testing data were identified, so an assumed de novo occurrence without confirmed maternity and paternity cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, pedigrees, genotype data, or meioses were identified, so co-segregation cannot be evaluated.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
No patient phenotype or family history specific to the variant case was available. The available ClinVar condition label is only "Neurodevelopmental disorder" and does not establish a highly specific phenotype with a single genetic etiology. The governing rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology."
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. The governing rule requires observation of the variant in a healthy adult individual, with the relevant zygosity for a recessive, dominant, or X-linked disorder and full penetrance expected at an early age. The case evidence contains no documented healthy-adult carrier, homozygote, or hemizygote observation and does not establish the disease inheritance model or penetrance needed for this criterion.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
NM_002830.4:c.872A>T (NP_002821.1:p.(Tyr291Phe)) has no documented variant-specific, well-established in vitro or in vivo functional assay demonstrating preserved protein function or normal splicing in the reviewed evidence. The only retrieved publication, PMID:25741868, is a general ACMG/AMP guideline and explicitly does not mention PTPN4 or this variant. No source supplies validated assay controls, biologically relevant normal-function endpoints, or reproducible benign results. Therefore, BS3 cannot be assessed from the available functional evidence.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members, pedigrees, genotype data, or phenotype assessments were identified, so lack of segregation cannot be evaluated and phenocopy or multilocus explanations cannot be considered.
Lack of segregation in affected members of a family.
BP2 cannot be assessed because the available evidence does not show NM_002830.4:c.872A>T (p.Tyr291Phe) in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No evidence was available that NM_002830.4:c.872A>T was found in a case with an alternate molecular basis for disease. The governing rule is: "Variant found in a case with an alternate molecular basis for disease."
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002830.4:c.872A>T in PTPN4 is a missense substitution predicted to produce NP_002821.1:p.(Tyr291Phe). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for PTPN4, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002830.4:c.872A>T in PTPN4 is a missense substitution predicted to produce NP_002821.1:p.(Tyr291Phe). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for PTPN4, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002830.4:c.872A>T in PTPN4 is a missense substitution predicted to produce NP_002821.1:p.(Tyr291Phe). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for PTPN4, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002830.4:c.872A>T in PTPN4 is a missense substitution predicted to produce NP_002821.1:p.(Tyr291Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PTPN4, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in PTPN4, mapped onto the exon structure of NM_002830.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This is a missense variant, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot be substituted. REVEL is 0.718, below the generic PP3 moderate threshold of >= 0.773 and above the supporting threshold of >= 0.644, so the result is indeterminate/gray-zone for PP3 and does not meet the criterion. BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... PP3 (moderate): >= 0.773 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... An indeterminate result on the applicable path means PP3/BP4 are simply not met.
This is a missense variant, so the governing generic rule requires the missense REVEL path only; SpliceAI cannot be substituted. REVEL is 0.718, above the generic BP4 supporting threshold of <= 0.29, so BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... An indeterminate result on the applicable path means PP3/BP4 are simply not met.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002830.4:c.872A>T in PTPN4 is a missense substitution predicted to produce NP_002821.1:p.(Tyr291Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for PTPN4, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.718. BayesDel score = 0.0139478.
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Location Proposed Criteria for Interpretation of Sequence Variants
Context General ACMG/AMP/CAP workgroup consensus and laboratory-survey methodology for developing sequence-variant classification guidelines; no PTPN4-specific experiment or cohort described.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4818970)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.718. BayesDel score = 0.0139478.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.