rs139459091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

AIP
NM_003977.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

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]

AIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4 link	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6	ENST00000279146.8	NP_003968.3	O00170
AIP	NM_001302960.2 link	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6		NP_001289889.1	O00170A0A804HJ38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8 link	c.26G>A	p.Arg9Gln	missense_variant	Exon 1 of 6	1	NM_003977.4	ENSP00000279146.3		O00170

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

AN:

251426

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135918

show subpopulations

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.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727232

show subpopulations

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:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74506

show subpopulations

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.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign: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

- -

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 â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, 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 neoplasiaâ€šÃ„Ã¬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. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

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. -

Nov 23, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.058

T;T

MetaSVM

Uncertain

-0.092

PrimateAI

Benign

0.35

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over