rs104894190

Positions:

• chr11-67490911-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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

ACMG classification

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/exons	MANE	Protein	UniProt
AIP	NM_003977.4	c.911G>A	p.Arg304Gln	missense_variant	6/6	ENST00000279146.8	NP_003968.3
AIP	NM_001302959.2	c.734G>A	p.Arg245Gln	missense_variant	6/6		NP_001289888.1
AIP	NM_001302960.2	c.*51G>A		3_prime_UTR_variant	6/6		NP_001289889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.911G>A	p.Arg304Gln	missense_variant	6/6	1	NM_003977.4	ENSP00000279146	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152236 Hom.: 0 Cov.: 33

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

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

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

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:2 Uncertain:7 Benign:5 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Somatotroph adenoma Pathogenic:2 Uncertain:2 Benign: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. -
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	- -
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. -

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AIP: BP4 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 18, 2021	- -
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. -

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: 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
MutationTaster	Benign	0.95	A
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

Other links and lift over

dbSNP: rs104894190; hg19: chr11-67258382;