rs145047094

chr11-67483205-G-A

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.47G>A(p.Arg16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,218 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts 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. R16C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (5 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: 1.77

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=0.022812605).
• BP6: Variant 11-67483205-G-A is Benign according to our data. Variant chr11-67483205-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41184.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00188 (287/152366) while in subpopulation NFE AF= 0.00331 (225/68030). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.47G>A	p.Arg16His	missense_variant	1/6	ENST00000279146.8
AIP	NM_001302960.2	c.47G>A	p.Arg16His	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.47G>A	p.Arg16His	missense_variant	1/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152248 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00197 AC: 496 AN: 251450 Hom.: 2 AF XY: 0.00201 AC XY: 273 AN XY: 135920

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00250 AC: 3661 AN: 1461852 Hom.: 5 Cov.: 31 AF XY: 0.00252 AC XY: 1832 AN XY: 727226

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152366 Hom.: 0 Cov.: 31 AF XY: 0.00178 AC XY: 133 AN XY: 74510

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00307 Hom.: 2

Bravo AF: 0.00171

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00332

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:3

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	GeneDx	Mar 04, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19366855, 27267386, 17609395, 28255869, 29848728, 19474519, 29036195, 26963951, 26792934, 22319033, 17242703, 21348957, 27253664, 29074612, 21753072, 19794292, 25184284, 25614825, 29632148, 20457215, 17360484, 18484068, 17244780, 22915287, 26815903, 20506337, 30941100) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AIP: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2021	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	May 21, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Familial isolated pituitary adenoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

May 20, 2021

- -

AIP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2020

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	0.075
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N;D
REVEL	Pathogenic	0.78
Sift	Benign	0.092	T;T
Sift4G	Uncertain	0.031	D;D
Vest4		0.38
MVP		0.97
MPC		0.79
ClinPred		0.055	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.40

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: rs145047094; hg19: chr11-67250676;