Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_138960.4 | MANE Select | 880 nt | 83–808 |
| NM_138960.3 | RefSeq Select | 881 nt | 50–775 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | None bp |
| Donor Loss (DL) | 0.0 | None bp |
| Acceptor Gain (AG) | 0.0 | None bp |
| Donor Gain (DG) | 0.0 | None bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (V197I), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the PVS1 definition.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change.' The evidence for this variant shows: no previously established pathogenic V197I in TGIF2LX. Therefore, this criterion is not applied due to absence of a known pathogenic variant at this residue.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (confirmed maternity and paternity) in a patient with the disease and no family history.' The evidence for this variant shows: no de novo data provided. Therefore, this criterion is not applied due to lack of parental confirmation data.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene product.' The evidence for this variant shows: no functional characterization available. Therefore, this criterion is not applied because functional study data are lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls.' The evidence for this variant shows: no case-control or affected cohort data. Therefore, this criterion is not applied due to absence of prevalence data in affected individuals.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation.' The evidence for this variant shows: no hotspot or critical domain information. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive).' The evidence for this variant shows: MAF=70.4% in gnomAD. Therefore, this criterion is not applied because the variant is common in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant (for recessive disorders).’ The evidence for this variant shows: no data on phase with other variants. Therefore, this criterion is not applied due to lack of trans-configuration data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: it is a missense change, not an indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen.' The evidence for this variant shows: no other pathogenic missense at V197. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: no gene-specific missense constraint or disease mechanism established. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: mixed in silico predictions with predominance of benign but some conflicting. Therefore, this criterion is not applied due to inconclusive computational evidence.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or clinical correlation provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without accessible evidence.' The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Stand Alone)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder.' The evidence for this variant shows: MAF=70.4% overall and up to 91.3% in African/African American population. Therefore, this criterion is applied at Stand Alone strength because the allele frequency far exceeds the >5% threshold.
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: MAF well above any expected disease prevalence threshold. Therefore, this criterion is applied at Strong strength because high population frequency argues against pathogenicity.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant/X‐linked disorder with full penetrance expected at an early age.' The evidence for this variant shows: population data from gnomAD but no documented healthy adult phenotype information. Therefore, this criterion is not applied due to lack of clinical status confirmation for carriers.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing.' The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members.' The evidence for this variant shows: no family study data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease.' The evidence for this variant shows: no known disease mechanism indicating only LoF in TGIF2LX. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant.' The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in a repetitive region without known function.' The evidence for this variant shows: missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact.' The evidence for this variant shows: mixed computational predictions. Therefore, this criterion is not applied due to lack of consensus benign predictions.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no case reports with alternate etiology. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence.' The evidence for this variant shows: not reported in any database. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing.' The evidence for this variant shows: missense change, not synonymous. Therefore, this criterion is not applied.