rs139407567

chr11-67490807-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_003977.4(AIP):c.807C>T(p.Phe269=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00103 in 1,612,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: AIP NM_003977.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7 O:1
• Conservation: PhyloP100: 4.72

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-67490807-C-T is Benign according to our data. Variant chr11-67490807-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41209.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, not_provided=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000578 (88/152352) while in subpopulation SAS AF= 0.00165 (8/4834). AF 95% confidence interval is 0.000823. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.807C>T	p.Phe269=	synonymous_variant	6/6	ENST00000279146.8
AIP	NM_001302960.2	c.799C>T	p.Gln267Ter	stop_gained	6/6
AIP	NM_001302959.2	c.630C>T	p.Phe210=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.807C>T	p.Phe269=	synonymous_variant	6/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000559 AC: 139 AN: 248838 Hom.: 0 AF XY: 0.000606 AC XY: 82 AN XY: 135236

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000887

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00108 AC: 1571 AN: 1460054 Hom.: 3 Cov.: 32 AF XY: 0.00110 AC XY: 802 AN XY: 726336

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0000574

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.000912

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74498

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00165

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000777 Hom.: 0

Bravo AF: 0.000695

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2019	This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 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 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Somatotroph adenoma Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284] -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 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	Jun 23, 2021	- -

AIP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

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
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139407567; hg19: chr11-67258278;