11-67487147-C-T

Position:

• chr11-67487147-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003977.4(AIP):​c.241C>T​(p.Arg81*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AIP NM_003977.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.22

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 11-67487147-C-T is Pathogenic according to our data. Variant chr11-67487147-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIP	NM_003977.4	c.241C>T	p.Arg81*	stop_gained	2/6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.241C>T	p.Arg81*	stop_gained	2/6		NP_001289889.1
AIP	NM_001302959.2	c.64C>T	p.Arg22*	stop_gained	2/6		NP_001289888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.241C>T	p.Arg81*	stop_gained	2/6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000306 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change creates a premature translational stop signal (p.Arg81*) in the AIP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIP are known to be pathogenic (PMID: 23321498, 26186299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with AIP-related conditions (PMID: 18381572). ClinVar contains an entry for this variant (Variation ID: 41167). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2024

The p.R81* variant (also known as c.241C>T), located in coding exon 2 of the AIP gene, results from a C to T substitution at nucleotide position 241. This changes the amino acid from an arginine to a stop codon within coding exon 2. This variant has been reported in multiple individuals diagnosed with pituitary adenomas (Leontiou CA et al. J Clin Endocrinol Metab, 2008 Jun;93:2390-401; Toledo RA et al. Clinics (Sao Paulo), 2010 Apr;65:407-15; Dutta P et al. J Clin Endocrinol Metab, 2019 Aug;104:3539-3544; Guaraldi F et al. Pituitary, 2012 Dec;15 Suppl 1:S61-7; Gaspar LM et al. J Endocrinol Invest, 2023 Nov;46:2299-2307; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. (Leontiou CA et al. J Clin Endocrinol Metab, 2008 Jun;93:2390-401). (Toledo RA et al. Clinics (Sao Paulo), 2010 Apr;65:407-15). (Dutta P et al. J Clin Endocrinol Metab, 2019 Aug;104:3539-3544). (Guaraldi F et al. Pituitary, 2012 Dec;15 Suppl 1:S61-7). (Gaspar LM et al. J Endocrinol Invest, 2023 Nov;46:2299-2307). -

Somatotroph adenoma Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	52
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.98
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267606541; hg19: chr11-67254618;