PAH c.1200-95T>C, p.?
NM_000277.3:c.1200-95T>C
Variant of Uncertain Significance (VUS)
With supportive absence from population databases (PM2_Supporting) and benign computational/splicing evidence (BP4_Supporting, BP7_Supporting), but lacking additional pathogenic or benign evidence, NM_000277.3:c.1200-95T>C remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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
Genome Browser
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HGVS InputNM_000277:c.1200-95T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.10
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Any canonical splice site predicted to disrupt reading frame and undergo nonsense mediated decay". The evidence for this variant shows it is located at c.1200-95T>C, outside canonical splice sites (+1/2). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Same predicted splicing impact as a previously classified (likely) pathogenic variant". There is no previously classified variant with the same splicing impact at this position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Confirmation of paternity only is insufficient. Only applicable when proband has a known pathogenic variant in trans with the de novo variant." No de novo evidence or parental testing is available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. In vitro enzyme activity <50% compared to wild type controls." No functional studies have been performed on this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of variant in affected individuals significantly increased compared with controls." There are no case-control data or reports in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Active site residues in PAH include: Tyr138, Arg158, Val245, Tyr268, Thr278, Pro279, Glu289, Ala300, Asp315, Phe331, Ala345, Gly346, Ser349, Tyr377; substrate binding residues: 46-48, 63-69; cofactor binding residues: His285, His290, Glu330, 246-266, 280-283, 322-326, 377-379." The variant is intronic at c.1200-95 and does not affect any defined functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Threshold <0.0002 (0.02%) The 0.0002 cutoff is based on disease frequency of 1:12,000 and the most common PAH pathogenic variant, R408W, the ExAC frequency is 0.0006594..." The evidence for this variant shows it is absent from population databases (gnomAD MAF = 0%). Therefore, this criterion is applied at Supporting strength because the allele frequency is below the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Applicable as described in SVI recommendations for in trans criterion." There is no evidence of this variant occurring in trans with a pathogenic PAH variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." This intronic variant does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." This is an intronic variant with no missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." There is no de novo evidence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong based on segregation data." No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation, where missense is a common mechanism of disease." This variant is intronic and does not meet missense criteria. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Predicted impact on splicing by SpliceAI (score >0.5) or REVEL score thresholds for missense." SpliceAI predicts a maximum score of 0.01 (<0.5), indicating minimal splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Plasma phenylalanine concentration persistently above 120 µmol/L with specific biochemical workup." No clinical biochemical data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The variant is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Allele frequency ≥1.5% in general population." The variant is absent in gnomAD (MAF = 0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency ≥0.2% in general population." The variant is absent in population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observed in homozygous state in a healthy adult." There is no evidence of this variant in homozygous state in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "In vitro enzyme activity >85% compared to wild type controls." No functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members or presence in unaffected individuals." No segregation or unaffected individual data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease." This variant is intronic, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder." No such evidence exists. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive region without functional impact." This variant is intronic and not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "No predicted impact on splicing by SpliceAI (score <0.1)". SpliceAI predicts a maximum score of 0.01 for this variant, indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence suggests no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." No such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The variant is not reported in any reputable database. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Per SVI recommendations (PMID: 36865205), use BP7 only if BP4 is met; intronic variants must be outside +7/-21 nt exonic variants must be outside first and last 3 bases of exon." This variant is at –95, outside the +7/–21 nt window, and BP4 is met. Therefore, this criterion is applied at Supporting strength.