rs267606589

Positions:

• chr11-67490918-G-GC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_003977.4(AIP):​c.919dup​(p.Arg307ProfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIP NM_003977.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.14

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 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0755 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-67490918-G-GC is Pathogenic according to our data. Variant chr11-67490918-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41215.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIP	NM_003977.4	c.919dup	p.Arg307ProfsTer?	frameshift_variant	6/6	ENST00000279146.8	NP_003968.3
AIP	NM_001302959.2	c.742dup	p.Arg248ProfsTer?	frameshift_variant	6/6		NP_001289888.1
AIP	NM_001302960.2	c.*59dup		3_prime_UTR_variant	6/6		NP_001289889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.919dup	p.Arg307ProfsTer?	frameshift_variant	6/6	1	NM_003977.4	ENSP00000279146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Somatotroph adenoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

GeneReviews

Jun 21, 2012

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2023

The c.919dupC variant, located in coding exon 6 of the AIP gene, results from a duplication of C at nucleotide position 919, causing a translational frameshift with a predicted alternate stop codon (p.Q307Pfs*70). This alteration occurs at the 3' terminus of theAIP gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 45 amino acids. This frameshift impacts the last 24amino acids of the native protein. However, frameshifts are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been identified in pediatric patients with pituitary macroadenomas (Stratakis CA et al. Clin Genet, 2010 Nov;78:457-63; Beckers A et al. Endocr Rev, 2013 Apr;34:239-77). Of note, this variant is designated as c.919insC, p.Gln307ProfsX104, and Q307fsX104 in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change results in a frameshift in the AIP gene (p.Arg307Profs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the AIP protein and extend the protein by an uncertain number of additional amino acid residue(s). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AIP-related conditions. ClinVar contains an entry for this variant (Variation ID: 41215). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

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: rs267606589; hg19: chr11-67258389;