rs148986773

Positions:

• chr11-67490896-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003977.4(AIP):​c.896C>T​(p.Ala299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,612,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A299T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 0.0400

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061604917).
• BP6: Variant 11-67490896-C-T is Benign according to our data. Variant chr11-67490896-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41214.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, not_provided=1, Uncertain_significance=1}. Variant chr11-67490896-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00065 (99/152264) while in subpopulation AMR AF= 0.00105 (16/15304). AF 95% confidence interval is 0.000755. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.896C>T	p.Ala299Val	missense_variant	6/6	ENST00000279146.8
AIP	NM_001302959.2	c.719C>T	p.Ala240Val	missense_variant	6/6
AIP	NM_001302960.2	c.*36C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.896C>T	p.Ala299Val	missense_variant	6/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000561 AC: 139 AN: 247974 Hom.: 0 AF XY: 0.000511 AC XY: 69 AN XY: 134954

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000928 AC: 1355 AN: 1460360 Hom.: 1 Cov.: 32 AF XY: 0.000907 AC XY: 659 AN XY: 726468

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74438

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000837 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000455 AC: 55

EpiCase AF: 0.000763

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	AIP: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AIP p.A299V variant was identified in 1 of 72 proband chromosomes (frequency: 0.0139) from endocrine neoplasia-predisposition patients from the Netherlands who were negative for MEN1 mutations (Georgitsi_2007_PMID:17360484). The p.A299V variant was also identified in a family with familial isolated pituitary adenoma and was identified in two compound heterozygous asymptomatic males in this family who also carried the AIP p.R304* variant. Functional assessment of the effect of AIP binding with PDE4A5 did not demonstrate decreased binding compared to wildtype (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs148986773), ClinVar (classified as likely benign by GeneDx and Illumina and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as likely benign and a VUS) but was not identified in Cosmic. The variant was identified in control databases in 152 of 279364 chromosomes at a frequency of 0.0005441 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 119 of 126880 chromosomes (freq: 0.000938), Other in 5 of 7124 chromosomes (freq: 0.000702), Latino in 20 of 35308 chromosomes (freq: 0.000566) and African in 8 of 24522 chromosomes (freq: 0.000326), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. Expression of the p.A299V AIP protein expressed in HEK293 cells demonstrated a decreased half-life compared to expression of WT AIP (Hernández-Ramírez_2016_PMID:27253664). The p.Ala240 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	This variant is associated with the following publications: (PMID: 27267386, 28220018, 29074612, 22720333, 27253664, 27535533, 27153395, 20506337, 24423289, 17360484) -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 21, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2021	- -

Somatotroph adenoma Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

AIP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.062	T
MetaSVM	Uncertain	0.056	D
MutationTaster	Benign	0.53	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.24	T
Vest4		0.13
MVP		0.72
MPC		0.38
ClinPred		0.014	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.56

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: rs148986773; hg19: chr11-67258367;