rs267606581

Variant names:

• chr11-67490829-G-C
• rs267606581
• NM_003977.4:c.829G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003977.4(AIP):​c.829G>C​(p.Ala277Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.70

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4	c.829G>C	p.Ala277Pro	missense_variant	Exon 6 of 6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.821G>C	p.Gly274Ala	missense_variant	Exon 6 of 6		NP_001289889.1
AIP	NM_001302959.2	c.652G>C	p.Ala218Pro	missense_variant	Exon 6 of 6		NP_001289888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.829G>C	p.Ala277Pro	missense_variant	Exon 6 of 6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Oct 05, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with proline at codon 277 of the AIP protein (p.Ala277Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with a pituitary adenoma (PMID: 19556287). ClinVar contains an entry for this variant (Variation ID: 41212). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A277P variant (also known as c.829G>C), located in coding exon 6 of the AIP gene, results from a G to C substitution at nucleotide position 829. The alanine at codon 277 is replaced by proline, an amino acid with highly similar properties. This variant was reported in an individual with features consistent with AIP-related familial isolated pituitary adenoma (FIPA) (Jaffrain-Rea ML et al. Endocr Relat Cancer, 2009 Sep;16:1029-43). This alteration is located in the functional significant tetratricopeptide repeat domain of the AIP protein, and a structural analysis suggests it may disrupt packing of the hydrophobic core (Morgan RM et al. PLoS One, 2012 Dec;7:e53339). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

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	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.22	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	.;D
REVEL	Uncertain	0.60
Sift	Benign	0.051	.;T
Sift4G	Benign	0.082	T;T
Vest4		0.77
MutPred		0.57		.;Loss of MoRF binding (P = 0.0604);
MVP		0.70
MPC		1.3
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.90

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: rs267606581; hg19: chr11-67258300;