rs104895073

Positions:

• chr11-67490059-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003977.4(AIP):​c.490C>T​(p.Gln164Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AIP NM_003977.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.18

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-67490059-C-T is Pathogenic according to our data. Variant chr11-67490059-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 41185.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.490C>T	p.Gln164Ter	stop_gained	4/6	ENST00000279146.8
AIP	NM_001302960.2	c.490C>T	p.Gln164Ter	stop_gained	4/6
AIP	NM_001302959.2	c.313C>T	p.Gln105Ter	stop_gained	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.490C>T	p.Gln164Ter	stop_gained	4/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455846 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

The p.Q164* variant (also known as c.490C>T), located in coding exon 4 of the AIP gene, results from a C to T substitution at nucleotide position 490. This changes the amino acid from a glutamine to a stop codon within coding exon 4. One study found that this mutation drastically reduced the protein-protein binding activity of the AIP protein and identified this alteration in 1/38 familial isolated pituitary adenoma (FIPA) families (Igreja S et al. Hum. Mutat., 2010 Aug;31:950-60). This mutation has also been reported in additional individuals with FIPA (Hernández-Ramírez LC et al. J. Clin. Endocrinol. Metab., 2015 Sep;100:E1242-54) and in a German patient with acromegaly and pituitary macroadenoma diagnosed at age 18 (Schöfl C et al. J. Clin. Endocrinol. Metab., 2014 Dec;99:E2789-93). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Somatotroph adenoma Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A
Vest4		0.90
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104895073; hg19: chr11-67257530;