11-67490827-C-T

Position:

chr11-67490827-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_003977.4(AIP):c.827C>T(p.Ala276Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

AIP
NM_003977.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.06

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 links:

AIP (HGNC:):

AIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28817096).

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AIP	NM_003977.4 linkuse as main transcript	c.827C>T	p.Ala276Val	missense_variant	6/6	ENST00000279146.8	NP_003968.3	O00170
AIP	NM_001302959.2 linkuse as main transcript	c.650C>T	p.Ala217Val	missense_variant	6/6		NP_001289888.1	O00170A0A804HKL7
AIP	NM_001302960.2 linkuse as main transcript	c.819C>T	p.Arg273Arg	synonymous_variant	6/6		NP_001289889.1	O00170A0A804HJ38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8 linkuse as main transcript	c.827C>T	p.Ala276Val	missense_variant	6/6	1	NM_003977.4	ENSP00000279146.3		O00170

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249144

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.000250

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460402

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect: increased rate of protein degradation compared to wildtype (PMID: 27253664); This variant is associated with the following publications: (PMID: 21512261, 27253664) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 276 of the AIP protein (p.Ala276Val). This variant is present in population databases (rs61741147, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with AIP-related conditions. ClinVar contains an entry for this variant (Variation ID: 485056). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AIP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects AIP function (PMID: 27253664). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Pituitary dependent hypercortisolism;C1863342:Acroleukopathy, symmetric;C4538355:Somatotroph adenoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Somatotroph adenoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.068

T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.51

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.9

.;N

REVEL

Uncertain

0.31

Sift

Benign

0.20

.;T

Sift4G

Benign

0.25

T;T

Vest4

0.57

MVP

0.67

MPC

1.1

ClinPred

0.20

GERP RS

5.3

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over