11-67490911-G-A

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

Scores

4
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7B:5O:2

Conservation

PhyloP100: 3.41
Variant links:
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]

Genome browser will be placed here

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
AIPNM_003977.4 linkc.911G>A p.Arg304Gln missense_variant Exon 6 of 6 ENST00000279146.8 NP_003968.3 O00170
AIPNM_001302959.2 linkc.734G>A p.Arg245Gln missense_variant Exon 6 of 6 NP_001289888.1 O00170A0A804HKL7
AIPNM_001302960.2 linkc.*51G>A 3_prime_UTR_variant Exon 6 of 6 NP_001289889.1 O00170A0A804HJ38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AIPENST00000279146.8 linkc.911G>A p.Arg304Gln missense_variant Exon 6 of 6 1 NM_003977.4 ENSP00000279146.3 O00170

Frequencies

GnomAD3 genomes
AF:
0.00108
AC:
165
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
Gnomad ASJ
AF:
0.0199
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00119
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.00165
AC:
409
AN:
247298
Hom.:
2
AF XY:
0.00167
AC XY:
225
AN XY:
134698
show subpopulations
Gnomad AFR exome
AF:
0.0000635
Gnomad AMR exome
AF:
0.000668
Gnomad ASJ exome
AF:
0.0211
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000470
Gnomad NFE exome
AF:
0.00135
Gnomad OTH exome
AF:
0.00366
GnomAD4 exome
AF:
0.00116
AC:
1687
AN:
1460232
Hom.:
4
Cov.:
32
AF XY:
0.00117
AC XY:
850
AN XY:
726406
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000716
Gnomad4 ASJ exome
AF:
0.0185
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000384
Gnomad4 NFE exome
AF:
0.000939
Gnomad4 OTH exome
AF:
0.00194
GnomAD4 genome
AF:
0.00108
AC:
165
AN:
152354
Hom.:
0
Cov.:
33
AF XY:
0.000967
AC XY:
72
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.0199
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00119
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00221
Hom.:
1
Bravo
AF:
0.00107
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.00141
AC:
170
EpiCase
AF:
0.00218
EpiControl
AF:
0.00148

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
Mar 09, 2018
Aziz Sancar Institute of Experimental Medicine, Istanbul University
Significance: Pathogenic
Review Status: flagged submission
Collection Method: research

a variant already in ClinVar database associated with clinical findings in a Turkish patient -

May 28, 2019
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2007
OMIM
Significance: Pathogenic
Review Status: flagged submission
Collection Method: literature only

- -

Jun 22, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:3Benign:2
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 21, 2016
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

AIP: BP4, BS1, BS2 -

Hereditary cancer-predisposing syndrome Benign:2
Jun 18, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Feb 20, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not specified Uncertain:1
Sep 25, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 31, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dopamine agonists response Other:1
Mar 09, 2018
Aziz Sancar Institute of Experimental Medicine, Istanbul University
Significance: drug response
Review Status: no assertion criteria provided
Collection Method: research

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.079
D
MetaRNN
Benign
0.0086
T
MetaSVM
Benign
-0.69
T
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.9
N
REVEL
Uncertain
0.31
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.0090
D
Vest4
0.72
MVP
0.90
MPC
0.41
ClinPred
0.028
T
GERP RS
2.5
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894190; hg19: chr11-67258382; API