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LYFE SCIENCES
Project: HERA
NM_003977.4:c.811C>T
p.Arg271Trp  ·  AIP
ACMG/AMP
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Classification rationale
1

The AIP c.811C>T (p.Arg271Trp) variant has been reported in ClinVar as Pathogenic or Likely pathogenic and has also been described in multiple published AIP-associated pituitary adenoma cohorts, including familial isolated pituitary adenoma families and a large kindred with aggressive pituitary tumors.

clinvar ↗ PMID:17244780 ↗ PMID:19684062 ↗ PMID:21753072 ↗ PMID:26186299 ↗
2

This variant is rare in population databases, with an allele frequency of 4.01706e-06 in gnomAD v2.1 and 3.10087e-06 in gnomAD v4.1, both well below the 0.1% threshold used for PM2 in this generic review.

gnomad_v2 ↗ gnomad_v4 ↗
3

Computational evidence supports a deleterious missense effect, with REVEL 0.785 and BayesDel 0.292581, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 4.01706e-06; MAF= 0.00040%, 1/248938 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26797e-05; MAF= 0.00327%, 1/30600 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.10087e-06; MAF= 0.00031%, 5/1612452 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09827e-05; MAF= 0.00110%, 1/91052 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AIP, an aryl hydrocarbon receptor-interacting protein, is infrequently altered in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.785. BayesDel score = 0.292581.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR271
Hotspots ↗