11-67490911-G-A
Variant names:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_003977.4(AIP):c.911G>A(p.Arg304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,586 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0012 ( 4 hom. )
Consequence
AIP
NM_003977.4 missense
NM_003977.4 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 3.41
Genes affected
AIP (HGNC:358): (aryl hydrocarbon receptor interacting protein) The protein encoded by this gene is a receptor for aryl hydrocarbons and a ligand-activated transcription factor. The encoded protein is found in the cytoplasm as part of a multiprotein complex, but upon binding of ligand is transported to the nucleus. This protein can regulate the expression of many xenobiotic metabolizing enzymes. Also, the encoded protein can bind specifically to and inhibit the activity of hepatitis B virus. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.008575559).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152354) while in subpopulation NFE AF= 0.00119 (81/68032). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 165 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AIP | NM_003977.4 | c.911G>A | p.Arg304Gln | missense_variant | Exon 6 of 6 | ENST00000279146.8 | NP_003968.3 | |
| AIP | NM_001302959.2 | c.734G>A | p.Arg245Gln | missense_variant | Exon 6 of 6 | NP_001289888.1 | ||
| AIP | NM_001302960.2 | c.*51G>A | 3_prime_UTR_variant | Exon 6 of 6 | NP_001289889.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00108 AC: 165AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00165 AC: 409AN: 247298Hom.: 2 AF XY: 0.00167 AC XY: 225AN XY: 134698
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GnomAD4 exome AF: 0.00116 AC: 1687AN: 1460232Hom.: 4 Cov.: 32 AF XY: 0.00117 AC XY: 850AN XY: 726406
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GnomAD4 genome 0.00108 AC: 165AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000967 AC XY: 72AN XY: 74494
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:7Benign:5Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Somatotroph adenoma Pathogenic:2Uncertain:2Benign:1
| Pathogenic, flagged submission | literature only | OMIM | Mar 06, 2007 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jun 22, 2023 | The AIP c.911G>A (p.Arg304Gln) missense change has a maximum subpopulation frequency of 0.14% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A ß-galactosidase activity assay in yeast showed a mild reduction of ß-galactosidase activity compared to wildtype (PMID: 20506337). This variant has been reported in individuals with pituitary adenoma (PMID: 17360484, 17609395, 18381572, 19366855, 20506337). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
| Pathogenic, flagged submission | research | Aziz Sancar Institute of Experimental Medicine, Istanbul University | Mar 09, 2018 | a variant already in ClinVar database associated with clinical findings in a Turkish patient - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Uncertain:3Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | AIP: BP4, BS1, BS2 - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2016 | The R304Q variant in the AIP gene has been reported in the literature in several patients with familial isolated pituitary adenoma, sporadic pituitary adenoma, acromegaly, and/or hyperparathyroidism (Georgitsi et al., 2007; Igreja et al., 2010; Occhi et al., 2010; Tichomirowa et al., 2011; Cazabat et al., 2012; Cuny et al., 2013; Pardi et al., 2013; Preda et al., 2014; Schofl et al., 2014). This variant is located in the aryl hydrocarbon receptor (AHR) binding region and has been hypothesized to impact AIP and AHR interactions (Georgitisi et al., 2007). However, AIP also interacts with PDE4A5 and in vitro AIP-PDE4A5 functional assays suggest that the R304Q variant only has a minimal effect on AIP-PDE4A5 binding (Igreja et al., 2010). Although the R304Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, this variant has been observed in 3/44 (6.8%) of unaffected centenarian patients of Ashkenazi Jewish ancestry (Freudenberg-Hua et al., 2014). The R304Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the R304Q variant is damaging to the protein structure/function. Therefore, we interpret R304Q as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 18, 2021 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 25, 2018 | The p.Arg304Gln variant in AIP has been reported in >10 individuals with pituita ry adenoma and segregated with disease in two affected members across two famili es (Georgitsi 2007, Igreja 2010, Occhi 2010, Tichomirowa 2011, Cazabat 2012, Cun y 2013, Pardi 2013, Preda 2014, Schofl 2014, Arajuo 2017). This variant has also been identified in multiple individuals without pituitary lesions (Tichomirowa 2011, Freudenberg-Hua 2014, Pardi 2013) and in 2.07% (208/10074) of Ashkenazi Je wish chromosomes, including 2 homozygous individuals, by gnomAD (http://gnomad.b roadinstitute.org). However, this frequency does not rule out a pathogenic role due to the prevalence of pituitary adenoma in the general population (~11% on au topsy; Molitch 2008) and the reduced penetrance of pituitary adenoma in individu als carrying pathogenic AIP variants (15-30%; Korbonits 2018). In vitro function al studies suggest that the p.Arg304Gln variant does not have a strong impact on protein function (Georgitisi 2007, Igreja 2010, Morgan 2012); however these typ es of assays may not accurately represent biological function. Computational pre diction tools and conservation analysis do not provide strong support for or aga inst an impact to the protein. Finally, this variant is present in ClinVar with conflicting interpretations of pathogenicity (Variation ID# 4893). In summary, t he clinical significance of the p.Arg304Gln variant is uncertain. ACMG/AMP Crit eria applied: PS4_Moderate, BS3_Supporting. - |
AIP-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 31, 2024 | The AIP c.911G>A variant is predicted to result in the amino acid substitution p.Arg304Gln. This variant, located within a CpG mutational hotspot, has been documented in multiple individuals with sporadic and familial pituitary adenomas (Georgitsi et al. 2007. PubMed ID: 17360484; Leontiou et al. 2008. PubMed ID: 18381572; Pardi et al. 2013. PubMed ID: 23633209; Cuny et al. 2013. PubMed ID: 23321498) and in at least one family member (patient’s mother) with normal pituitary MRI (Cuny et al. 2013. PubMed ID: 23321498). It has also been reported in an individual with prolactinoma (Araujo et al. 2017. PubMed ID: 29074612) and another with acromegaly (Preda et al 2014. PubMed ID: 25184284). This variant has also been described in an extended Danish family with several members with acromegalic features and somatotropinomas (Dal et al. 2020. PubMed ID: 32324286). The disease penetrance in this family was estimated to be 6%. Potential disease-modifying variants were also identified in 2 additional genes (PDE11A and ALG14). A yeast two-hybrid study of this variant demonstrated minimally deficient wild type activity (Igreja et al. 2010. PubMed ID: 20506337), however, tumors carrying this variant have been reported to display decreased AIP expression (Pardi et al. 2013. PubMed ID: 23633209). This variant is reported in 2.1% of alleles in individuals of Ashkenazi Jewish descent, including 2 homozygote observations, in gnomAD. In ClinVar, this variant is has conflicting interpretations of ranging from benign to uncertain significance, with the majority of submitters interpreting it as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/4893/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Pituitary dependent hypercortisolism Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Dopamine agonists response Other:1
| drug response, no assertion criteria provided | research | Aziz Sancar Institute of Experimental Medicine, Istanbul University | Mar 09, 2018 | a variant already in ClinVar database associated with drug response in a Turkish patient a plausible role in positive response to dopamine agonist therapy |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at