rs267606581

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

Scores

5
8
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 7.70
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]

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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
AIPNM_003977.4 linkuse as main transcriptc.829G>C p.Ala277Pro missense_variant 6/6 ENST00000279146.8 NP_003968.3
AIPNM_001302960.2 linkuse as main transcriptc.821G>C p.Gly274Ala missense_variant 6/6 NP_001289889.1
AIPNM_001302959.2 linkuse as main transcriptc.652G>C p.Ala218Pro missense_variant 6/6 NP_001289888.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AIPENST00000279146.8 linkuse as main transcriptc.829G>C p.Ala277Pro missense_variant 6/61 NM_003977.4 ENSP00000279146 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 05, 2020In 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 submitterclinical testingAmbry GeneticsMar 27, 2024The 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 providedliterature onlyGeneReviews-- -

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
MutationTaster
Benign
1.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606581; hg19: chr11-67258300; API