NM_003977.4:c.241C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. R81R) has been classified as Likely benign. 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 1.22

Publications

13 publications found

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]

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

AIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 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;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 11-67487147-C-T is Pathogenic according to our data. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar as Pathogenic. Clinvar id is 41167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67487147-C-T is described in CliVar 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 rank	MANE	Protein	UniProt
AIP	NM_003977.4 link	c.241C>T	p.Arg81*	stop_gained	Exon 2 of 6	ENST00000279146.8	NP_003968.3	O00170
AIP	NM_001302960.2 link	c.241C>T	p.Arg81*	stop_gained	Exon 2 of 6		NP_001289889.1	O00170A0A804HJ38
AIP	NM_001302959.2 link	c.64C>T	p.Arg22*	stop_gained	Exon 2 of 6		NP_001289888.1	O00170A0A804HKL7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8 link	c.241C>T	p.Arg81*	stop_gained	Exon 2 of 6	1	NM_003977.4	ENSP00000279146.3		O00170

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000211

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 22, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

PhyloP100

1.2

Vest4

0.98

GERP RS

4.3

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over