PAH c.1200-95T>C, p.?
NM_000277.3:c.1200-95T>C
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
PAH
Transcript
NM_000277.3
MANE Select
Total Exons
13
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000277.2 | Alternative | 13 exons | Reverse |
| NM_000277.1 | Alternative | 13 exons | Reverse |
Variant Details
HGVS Notation
NM_000277.3:c.1200-95T>C
Protein Change
?
Location
Exon 11
(Exon 11 of 13)
5'
Exon Structure (13 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000277.3
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Studies
Summary
The variant 1200-95T>C has not been functionally characterized.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.10
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines for PVS1, 'Any nonsense or frameshift variant occurring upstream of c.1285 ...' requires known variant type and transcript information. The evidence for this variant shows that the variant type and transcript details are unknown. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines for PS1, 'Same predicted splicing impact as a previously classified (likely) pathogenic variant' requires a known protein change. The evidence indicates that the protein change is unknown. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PS2, de novo occurrence with confirmed maternity and paternity is required. The evidence for this variant provides no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines for PS3, functional studies are required with sufficient analyses. The provided functional studies note indicates that the variant has not been functionally characterized. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PS4, increased prevalence in affected individuals is necessary. The evidence shows no such case-control data for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines for PM1, which states 'Active site residues and substrate/cofactor binding residues in PAH are defined', known protein change information is required. The evidence for this variant does not provide protein or domain localization data. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2, 'Threshold <0.0002 (0.02%) based on disease frequency' is used, and the variant is absent from population databases. The evidence shows a MAF of 0% and absence in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to VCEP guidelines for PM3, which requires evidence of the variant being in trans with a pathogenic variant, no such data is provided for this variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines for PM4, it applies to in-frame deletions/insertions with an impact on the protein. The variant’s effect is unknown and does not meet these conditions. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines for PM5, a different missense change in a residue with established pathogenicity is required. There is no such data provided for this variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PM6, evidence of a de novo occurrence (with additional confirmation requirements) is required, and no such evidence is present. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines for PP1, co-segregation analysis requires observation in multiple affected family members. The evidence does not include any segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PP2, this criterion applies to genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. There is insufficient evidence for this variant to apply this criterion. Therefore, it is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines for PP3, a strong deleterious in silico prediction (e.g., REVEL score thresholds) is required. The evidence indicates mixed or benign computational predictions with a benign CADD score and minimal SpliceAI impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to VCEP guidelines for PP4, a phenotype highly specific for a disease must be present. The provided evidence does not include any phenotypic information linking the variant to the disorder. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PP5, a reputable source’s assertion is needed. The variant is not reported in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines for BA1, an allele frequency of ≥1.5% is required. The evidence shows a frequency of 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines for BS1, an allele frequency of ≥0.2% is required. The variant is absent, with a frequency of 0%, so this criterion is not met and is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BS2, observing the variant in a homozygous state in healthy adults is required. There is no evidence of this in the provided data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines for BS3, in vitro enzyme activity >85% compared to wild type is necessary to support benignity. Functional studies for this variant are not available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BS4, this criterion is used when there is a lack of segregation in affected individuals. No such data is provided for this variant. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP1, this applies to missense variants in genes where loss of function is the primary mechanism. Given the variant type is unknown and no missense effect is established, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP2, observation of the variant in trans with a pathogenic variant is needed. There is no evidence for this observation. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP3, in-frame deletions/insertions in a repetitive region without a known function are required. The variant does not have data supporting this context. Therefore, this criterion is not applied.
BP4
BP4 (Strong)
Strength Modified
According to VCEP guidelines for BP4, 'Multiple lines of computational evidence suggest no impact on gene or gene product' with a strong level if supported by in silico predictors. The evidence shows a benign CADD score (-0.10) and minimal SpliceAI impact (0.01), supporting no splicing or deleterious impact. Therefore, this criterion is applied at Strong strength.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP5, this criterion applies if an alternate molecular cause is present, which is not the case here. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP6, benign evidence from a reputable source is required. No such evidence is available for this variant. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines for BP7, which is used for intronic variants outside of the splice region or exonic variants at the end if BP4 is already met, there is insufficient additional evidence to isolate this criterion. Therefore, this criterion is not applied.