11-67490910-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_003977.4(AIP):c.910C>T(p.Arg304Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

AIP
NM_003977.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 2.25

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 Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0836 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PP5

Variant 11-67490910-C-T is Pathogenic according to our data. Variant chr11-67490910-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490910-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AIP	NM_003977.4 linkuse as main transcript	c.910C>T	p.Arg304Ter	stop_gained	6/6	ENST00000279146.8
AIP	NM_001302959.2 linkuse as main transcript	c.733C>T	p.Arg245Ter	stop_gained	6/6
AIP	NM_001302960.2 linkuse as main transcript	c.*50C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8 linkuse as main transcript	c.910C>T	p.Arg304Ter	stop_gained	6/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247262

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1460262

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726414

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000166

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 27 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Observed in multiple families with Familial Isolated Pituitary Adenoma (FIPA) and in individuals with pituitary adenomas, acromegaly, and gigantism (Vierimaa et al., 2006; Daly et al., 2007; Tichomirowa et al., 2011; Niyazoglu et al., 2014; Marques et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Described as a pathogenic founder variant in Northern Ireland and Italy; however, it may also represent a mutational hot spot (Occhi et al., 2010; Chahal et al., 2011; Ramirez-Renteria et al., 2016; Radian et al., 2017); Published functional studies demonstrate increased cell proliferation, abolished interaction with PDE4A5, and reduced protein half-life (Leontiou et al., 2008; Hernndez-Ramrez et al., 2016); This variant is associated with the following publications: (PMID: 18381572, 27650164, 21208107, 33010004, 27033541, 30941100, 27253664, 30223298, 5320367, 21753072, 12638720, 17360484, 17244780, 16728643, 23743763, 20354355, 23321498, 23371967) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Arg304*) in the AIP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the AIP protein. This variant is present in population databases (rs104894195, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with pituitary adenomas and pituitary adenomas and acromegaly (PMID: 16728643, 18381572, 20354355, 21208107, 23321498, 23743763, 27033541, 27650164). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4888). For these reasons, this variant has been classified as Pathogenic. -

Somatotroph adenoma

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2018	The AIP c.910C>T (p.Arg304Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg304Ter variant has been reported in at least four studies and is found in over 100 probands including at least two in a homozygous state and the rest in a heterozygous state (Occhi et al. 2010; Chahal et al. 2011; Beckers et al. 2013; Hernandez-Ramirez et al. 2015). The majority of probands exhibited familial isolated pituitary adenomas (FIPA), though some probands were found with sporadic pituitary adenomas. Individuals that carried the p.Arg304Ter variant without FIPA were found to exhibit other phenotypes including breast cancer, glioma, osteosarcoma, and neuroendocrine tumor of the colon (Hernandez-Ramirez et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000024 in the European (Non-Finnish) population of the Genome Aggregation Database. Over-expression of the p.Arg304Ter variant AIP protein in HEK293 cells demonstrated that the variant protein has a significantly reduced half-life of 5.9 hours compared to wildtype at 48 hours, and that this could be rescued by proteasomal inhibition (Hernandez-Ramirez et al. 2016). Based on the collective evidence and application of the ACMG criteria, the c.910C>T (p.Arg304Ter) variant is classified as pathogenic for familial isolated pituitary adenomas. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 06, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration has been well described in numerous individuals with personal and/or family history consistent with AIP-Related Familial Isolated Pituitary Adenomas (Vierimaa O et al. Science, 2006 May;312:1228-30; Georgitsi M et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Mar;104:4101-5; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50; Cuny T et al. Eur. J. Endocrinol., 2013 Apr;168:533-41; Niyazoglu M et al. Pituitary, 2014 Jun;17:220-6; Radian S et al. Hum. Mutat., 2017 01;38:78-85). Haplotype studies have concluded this alteration to be both an Italian and Irish founder mutation (Occhi G et al. J. Endocrinol. Invest., 2010 Dec;33:800-5; Chahal HS et al. N. Engl. J. Med., 2011 Jan;364:43-50); however, given the presence of this alteration in other populations, including Turkish and Mexican, who do not share a common haplotype, it has been suggested that this alteration may arise from independent, recurring mutational events (Ramírez-Rentería C et al. Endocrine, 2016 Aug;53:402-11). Functional analysis of the effect of this alteration on cell proliferation has shown reduced ability to block cell proliferation compared with wild-type AIP (Leontiou CA et al. J. Clin. Endocrinol. Metab., 2008 Jun;93:2390-401). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of AIP, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 27 amino acids of the protein. While the exact functional impact of these removed amino acids is unknown at this time, the final carboxy-terminal amino acids are presumed necessary for interactions of AIP with heat shock protein 90 (hsp90) and the aryl hydrocarbon receptor (AhR) (Petrulis JR et al. Chem. Biol. Interact., 2002 Sep;141:25-40; Daly AF et al. J. Clin. Endocrinol. Metab., 2007 May;92:1891-6). As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.79

MutationTaster

Benign

1.0

Vest4

0.82

GERP RS

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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