rs139459091

chr11-67483184-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong 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. 13/19 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

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057757854).
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.26G>A	p.Arg9Gln	missense_variant	1/6	ENST00000279146.8
AIP	NM_001302960.2	c.26G>A	p.Arg9Gln	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.26G>A	p.Arg9Gln	missense_variant	1/6	1	NM_003977.4	P1

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

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251426 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135918

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 SAS 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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.000497

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

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000256 Hom.: 0

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

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2022	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) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 18, 2021	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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Somatotroph adenoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jan 19, 2023

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
MutationTaster	Benign	0.51	D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.30

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: rs139459091; hg19: chr11-67250655;