Classification rationale

PM2PP3 VUS

AIP c.811C>T

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.¹ 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.² 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 0.00.³

PM2 + PP3 → VUS

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

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_003977.4 · variants mapped to exon structure

AIP NM_003977.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This 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.

v2.1

This 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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,612,452
0 hom · FAF 7.9e-05%

South Asian 1 / 91,052	0.0011%
European (non-Finnish) 4 / 1,179,952	0.00034%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 248,938
0 hom

South Asian

1 / 30,600

0.0033%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).

ClinVar ↗

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 ↗

Functional 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 ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots