11-67490811-C-T

Position:

• chr11-67490811-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM2 PP3_Strong PP5_Very_Strong BS2

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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.928

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 ClinVar as [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 Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIP	NM_003977.4	c.811C>T	p.Arg271Trp	missense_variant	6/6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.803C>T	p.Ala268Val	missense_variant	6/6		NP_001289889.1
AIP	NM_001302959.2	c.634C>T	p.Arg212Trp	missense_variant	6/6		NP_001289888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.811C>T	p.Arg271Trp	missense_variant	6/6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248938 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135278

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460118 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 29, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIP protein function. Experimental studies have shown that this missense change affects AIP function (PMID: 20506337, 27253664). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	AIP: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2024

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.13	D
PrimateAI	Pathogenic	0.87	D
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	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.93

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: rs267606579; hg19: chr11-67258282;