rs267606579

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PM2PP3_StrongPP5_Very_StrongBS2

The NM_003977.4(AIP):c.811C>T(p.Arg271Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,118 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AIP
NM_003977.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 0.928

Publications

21 publications found

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 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

AIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 11-67490811-C-T is Pathogenic according to our data. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67490811-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 41210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4 link	c.811C>T	p.Arg271Trp	missense_variant	Exon 6 of 6	ENST00000279146.8	NP_003968.3	O00170
AIP	NM_001302960.2 link	c.803C>T	p.Ala268Val	missense_variant	Exon 6 of 6		NP_001289889.1	O00170A0A804HJ38
AIP	NM_001302959.2 link	c.634C>T	p.Arg212Trp	missense_variant	Exon 6 of 6		NP_001289888.1	O00170A0A804HKL7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8 link	c.811C>T	p.Arg271Trp	missense_variant	Exon 6 of 6	1	NM_003977.4	ENSP00000279146.3		O00170

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248938

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460118

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5424

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111926

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000720

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 271 of the AIP protein (p.Arg271Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial and sporadic pituitary adenomas (PMID: 17244780, 19684062, 21753072, 26186299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41210). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt AIP protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AIP function (PMID: 20506337, 27253664). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AIP: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -

Familial isolated pituitary adenoma

Pathogenic:1

Mar 26, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Oct 31, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R271W variant (also known as c.811C>T), located in coding exon 6 of the AIP gene, results from a C to T substitution at nucleotide position 811. The arginine at codon 271 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with a personal and/or family history of pituitary adenomas and segregates with disease in multiple families (De Sousa SMC et al. Eur J Endocrinol, 2017 May;176:635-644; Jennings JE et al. Eur J Endocrinol, 2009 Nov;161:799-804; Daly AF et al. J Clin Endocrinol Metab, 2007 May;92:1891-6; Ambry internal data). This variant induced severely reduced protein half-life which was a suggested mechanism for tumorigenesis (Hernández-Ramírez LC et al. J Clin Endocrinol Metab, 2016 08;101:3144-54). Based on internal structural analysis, R271W is highly destabilizing to the structure near a region known to interact with several other proteins and disrupts hydrogen bonds which are important to the stability of the TPR domain fold (Morgan RM et al. PLoS One, 2012 Dec;7:e53339; Das AK et al. EMBO J, 1998 Mar;17:1192-9; Bolger GB et al. J Biol Chem, 2003 Aug;278:33351-63; Igreja S et al. Hum Mutat, 2010 Aug;31:950-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Somatotroph adenoma

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.13

PhyloP100

0.93

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.4

.;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.95

MutPred

0.92

.;Loss of methylation at R271 (P = 0.0135);

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.93

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over