rs139459091

Variant names:

• chr11-67483184-G-A
• rs139459091
• NM_003977.4:c.26G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-67483184-G-A
• chr11-67483184-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003977.4(AIP):​c.26G>A​(p.Arg9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 1.41
• Publications: 10 publications found

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]

AIP Gene-Disease associations (from GenCC):

• growth hormone secreting pituitary adenoma 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial isolated pituitary adenoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromegaly

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057757854).
• BP6: Variant 11-67483184-G-A is Benign according to our data. Variant chr11-67483184-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 485052.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152356) while in subpopulation AMR AF = 0.00222 (34/15300). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 58 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6		NP_001289889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152238 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251426 AF XY: 0.000258

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461848 Hom.: 1 Cov.: 31 AF XY: 0.000198 AC XY: 144 AN XY: 727232

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000738 AC: 33 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000191 AC: 212 AN: 1111994

Other (OTH) AF: 0.000497 AC: 30 AN: 60394

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152356 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41596

American (AMR) AF: 0.00222 AC: 34 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000322 Hom.: 1

Bravo AF: 0.000446

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Dec 21, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pituitary adenomas and/or multiple neuroendocrine neoplasia in published literature (Cazabat et al., 2012; Oriola et al., 2013; Lecoq et al., 2016; Pardi et al., 2017; Martinez de LaPiscina et al., 2021); Published functional studies demonstrate partially reduced protein stability, cellular proliferation and cAMP-directed expression (Formosa et al., 2017); This variant is associated with the following publications: (PMID: 22319033, 29036195, 23038625, 30941100, 26792934, 34313605, 25614825, 29308445, 28255869) -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

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 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The AIP p.Arg9Gln variant was identified in dbSNP (ID: rs139459091) as “With Uncertain significance allele”, ClinVar (Uncertain Significance, Ambry Genetics), the LOVD 3.0 database (as Likely Pathogenic), the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 4 of 8586 European American and 0 of 4400 African American alleles. The variant was identified in gnomAD (Feb 27, 2017) control databases in 69 of 282814 chromosomes at a frequency of 0.000244. It was observed in the following populations: Latino in 28 of 35436 chromosomes (freq: 0.00079), Other in 5 of 7226 chromosomes (freq: 0.000692), European (non-Finnish) in 34 of 129136 chromosomes (freq: 0.000263), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and African in 1 of 24962 chromosomes (freq: 0.00004); it was not observed in the East Asian, European (Finnish) and South Asian populations. The AIP p.Arg9Gln variant was identified in a 21 year-old female with Acromegaly and a pituitary macroadenoma, but was not identified in the controls (Oriola_2012_PMID: 23038625). This patient presented with complete resistance to somatostatin analogues and had no family history of pituitary adenomas or other endocrine tumors. Similarly, the variant was identified in a 14 year-old female with PRL-secreting pituitary macroadenoma (diameter between 10 and 29 mm) originally presenting with primary amenorrhea and a 39 year-old female with ACTH-secreting microadenoma sized (diameter less than 10 mm) originally presenting with Cushing syndrome (Cazabat_2012_PMID: 22319033). Both of these patients had no family history of pituitary adenomas. In a study by Pardi et al., the p.Arg9Gln variant was identified in two Italian patients with sporadic cases of multiple endocrine neoplasia type 1 (no family history of multiple endocrine neoplasia–related manifestations), but was not identified in healthy controls (Pardi_2017_PMID: 29036195). The p.Arg9 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD and BLOSUM) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE and GeneSplicer) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Nov 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 18, 2021

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. -

Pituitary dependent hypercortisolism;C1863342:Acroleukopathy, symmetric;C4538355:Somatotroph adenoma Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Somatotroph adenoma Uncertain:1

Jan 19, 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.26G>A (p.Arg9Gln) missense change has a maximum subpopulation frequency of 0.079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with prolactin-secreting pituitary adenomas and hormonal dysfunction (PMID: 22319033, 34313605), an individual with a pituitary macroadenoma of unknown type (PMID: 23038625), and an individual with multiglandular familial primary hyperparathyroidism and a mixed prolactin- and GH-secreting pituitary adenoma (PMID: 29036195). The in silico tool REVEL predicts a benign effect on protein function, and in vitro functional studies demonstrated that this variant impacts the cAMP inhibitory ability of the wild-type AIP protein and may decrease the half-life of the protein (PMID: 28255869). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Uncertain	-0.092	T
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.026	D;T
Sift4G	Benign	0.54	T;T
Vest4		0.28
MVP		0.74
MPC		0.45
ClinPred		0.072	T
GERP RS		4.8
PromoterAI		-0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.30
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs139459091; hg19: chr11-67250655;