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 ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

AIP NM_003977.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 4.01706e-06 (1/248938, 0.00040%), and in gnomAD v4.1 the total allele frequency is 3.10087e-06 (5/1612452, 0.00031%), both well below the 0.1% rarity threshold used for PM2 in this generic review.

gnomAD v2.1 AF 4.01706e-06gnomAD v4.1 AF 3.10087e-06

gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

Multiple computational results support a deleterious effect on the protein. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect, while SpliceAI shows no predicted splice impact (max delta score 0.00). Overall, the in silico evidence supports pathogenicity at the protein level.

REVEL 0.785BayesDel 0.292581SpliceAI max delta 0.00

spliceai ↗

Assessed · not applied · 4 not met · 15 not assessed

Pathogenic

PS1 No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant through a different DNA change.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified.

PS3 Published functional literature was identified, but the reviewed evidence did not provide sufficiently specific, validated variant-level functional results for p.Arg271Trp to support a PS3 assertion.

PS4 This variant has been reported in multiple affected AIP-associated pituitary adenoma cohorts and families, including a large kindred with aggressive tumors, but the reviewed evidence did not provide a case-control enrichment analysis or another quantitative framework sufficient to apply PS4 under generic ACMG/AMP rules.

PM1 Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation.

PM5 No evidence was identified showing a different pathogenic missense change at the same amino acid residue that would support PM5.

PM6 No assumed de novo occurrence without confirmed parentage was identified.

PP1 Family-based observations were reported, but the reviewed evidence did not provide a segregation analysis sufficient for ACMG/AMP PP1.

PP2 Available evidence was insufficient to conclude that AIP is a gene in which missense variation is a common disease mechanism and benign missense variation is rare enough to apply PP2.

PP4 No individual-level phenotype description was provided for this case, so the specificity of the clinical presentation for AIP-related disease could not be assessed.

Benign

BA1 Population frequency is far below the benign stand-alone threshold.

BS1 Population frequency is below the benign strong threshold.

BS2 No evidence was identified showing this variant in a sufficient number of well-phenotyped unaffected individuals for a disorder setting appropriate to BS2.

BS3 No well-established functional study showing normal protein function for p.Arg271Trp was identified.

BS4 No evidence was identified showing lack of segregation with disease in informative affected family members.

BP1 Available evidence was insufficient to apply BP1.

BP2 No phase information with another pathogenic variant was identified to support BP2.

BP4 Available computational evidence does not support a benign interpretation.

BP5 No alternate molecular diagnosis explaining the phenotype was identified.

N/A · 7 PVS1 · PM3 · PM4 · PP5 · BP3 · BP6 · BP7

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

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