chr11-67483074-C-T

Variant names:

• chr11-67483074-C-T
• rs1565180279
• NM_003977.4:c.-85C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003977.4(AIP):​c.-85C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000877 in 1,140,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: AIP NM_003977.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.771
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• growth hormone secreting pituitary adenoma 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial isolated pituitary adenoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromegaly

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4	c.-85C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.-85C>T		5_prime_UTR_variant	Exon 1 of 6		NP_001289889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.-85C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1140128 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 581038

African (AFR) AF: 0.00 AC: 0 AN: 27100

American (AMR) AF: 0.00 AC: 0 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24060

East Asian (EAS) AF: 0.00 AC: 0 AN: 38002

South Asian (SAS) AF: 0.00 AC: 0 AN: 79506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5130

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 820630

Other (OTH) AF: 0.00 AC: 0 AN: 49558

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Somatotroph adenoma Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.90
PhyloP100		0.77
PromoterAI		-0.090	Neutral

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

Other links and lift over

dbSNP: rs1565180279; hg19: chr11-67250545;