rs267606581
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
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
NM_003977.4 missense
Scores
5
8
5
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AIP | NM_003977.4 | c.829G>C | p.Ala277Pro | missense_variant | 6/6 | ENST00000279146.8 | NP_003968.3 | |
AIP | NM_001302960.2 | c.821G>C | p.Gly274Ala | missense_variant | 6/6 | NP_001289889.1 | ||
AIP | NM_001302959.2 | c.652G>C | p.Ala218Pro | missense_variant | 6/6 | NP_001289888.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AIP | ENST00000279146.8 | c.829G>C | p.Ala277Pro | missense_variant | 6/6 | 1 | NM_003977.4 | ENSP00000279146 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 05, 2020 | 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. 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"). This variant has been observed in an individual with a pituitary adenoma (PMID: 19556287). ClinVar contains an entry for this variant (Variation ID: 41212). This variant is not present in population databases (ExAC no frequency). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2024 | 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
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D
REVEL
Uncertain
Sift
Benign
.;T
Sift4G
Benign
T;T
Vest4
0.77
MutPred
0.57
.;Loss of MoRF binding (P = 0.0604);
MVP
MPC
1.3
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at