Variant classification summary

NM_003977.4: c.811C>T

AIP · NP_003968.3:p.(Arg271Trp) · NM_003977.4

GRCh37: chr11:67258282 C>T · GRCh38: chr11:67490811 C>T

Gene: AIP Transcript: NM_003977.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

AIP

Transcript

NM_003977.4

Protein

NP_003968.3:p.(Arg271Trp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the generic PVS1 framework indicates that it does not fall into the default null-variant categories eligible for PVS1. Although AIP loss of function is an established disease mechanism, c.811C>T (p.Arg271Trp) is not a nonsense, frameshift, or canonical splice-site variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified.
PS3	Not assessed	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.	PMID:12810716 PMID:20506337 PMID:23300914
PS4	Not assessed	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.	PMID:17244780 PMID:19684062 PMID:21753072 PMID:26186299 clinvar
PM1	Not met	Available evidence does not show that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots PMID:23300914
PM2	Met	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 gnomad_v4
PM3	N/A	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disorder context.	PMID:20506337 PMID:26186299
PM4	N/A	This is not a protein length-changing variant and does not involve an in-frame insertion, in-frame deletion, or stop-loss event.
PM5	Not assessed	No evidence was identified showing a different pathogenic missense change at the same amino acid residue that would support PM5.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified.
PP1	Not assessed	Family-based observations were reported, but the reviewed evidence did not provide a segregation analysis sufficient for ACMG/AMP PP1. Unaffected carriers were also described, which is consistent with incomplete penetrance and limits straightforward segregation scoring.	PMID:19684062 PMID:26186299
PP2	Not assessed	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.	PMID:20506337
PP3	Met	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 bayesdel spliceai
PP4	Not assessed	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.
PP5	N/A	External pathogenic classifications were identified in ClinVar, but assertion-based criteria are not applied here in place of primary evidence review.	clinvar
BA1	Not met	Population frequency is far below the benign stand-alone threshold. The highest observed gnomAD v4.1 overall allele frequency is 3.10087e-06 (0.00031%), which is well below 1%.	gnomad_v4 gnomad_v2
BS1	Not met	Population frequency is below the benign strong threshold. The highest observed gnomAD v4.1 overall allele frequency is 3.10087e-06 (0.00031%), which is well below 0.3%.	gnomad_v4 gnomad_v2
BS2	Not assessed	No evidence was identified showing this variant in a sufficient number of well-phenotyped unaffected individuals for a disorder setting appropriate to BS2.	gnomad_v2 gnomad_v4 PMID:26186299
BS3	Not assessed	No well-established functional study showing normal protein function for p.Arg271Trp was identified.	PMID:12810716 PMID:20506337 PMID:23300914
BS4	Not assessed	No evidence was identified showing lack of segregation with disease in informative affected family members.	PMID:19684062 PMID:26186299
BP1	Not assessed	Available evidence was insufficient to apply BP1. Although loss of function is an established AIP disease mechanism, missense variants have also been reported in affected individuals, so this criterion was not used.	PMID:20506337 pvs1_gene_context
BP2	Not assessed	No phase information with another pathogenic variant was identified to support BP2.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region.
BP4	Not met	Available computational evidence does not support a benign interpretation. REVEL is 0.785 and BayesDel is 0.292581, both favoring a damaging missense effect; although SpliceAI predicts no splice disruption (max delta score 0.00), the overall in silico evidence does not support BP4.	revel bayesdel spliceai
BP5	Not assessed	No alternate molecular diagnosis explaining the phenotype was identified.
BP6	N/A	No external benign classification was used as independent evidence, and assertion-based criteria were not applied in place of primary evidence review.	clinvar
BP7	N/A	This is a missense variant rather than a synonymous or noncoding variant, so BP7 does not apply.	spliceai

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