11-67483184-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_003977.4(AIP):​c.26G>T​(p.Arg9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

AIP
NM_003977.4 missense

Scores

6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-67483184-G-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.27175385).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AIPNM_003977.4 linkc.26G>T p.Arg9Leu missense_variant Exon 1 of 6 ENST00000279146.8 NP_003968.3 O00170
AIPNM_001302960.2 linkc.26G>T p.Arg9Leu missense_variant Exon 1 of 6 NP_001289889.1 O00170A0A804HJ38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AIPENST00000279146.8 linkc.26G>T p.Arg9Leu missense_variant Exon 1 of 6 1 NM_003977.4 ENSP00000279146.3 O00170

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Oct 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R9L variant (also known as c.26G>T), located in coding exon 1 of the AIP gene, results from a G to T substitution at nucleotide position 26. The arginine at codon 9 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.043
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.068
T;.
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.079
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.75
T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Uncertain
-0.12
T
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.25
Sift
Uncertain
0.0090
D;T
Sift4G
Benign
0.30
T;T
Vest4
0.32
MutPred
0.55
Loss of MoRF binding (P = 0.0169);Loss of MoRF binding (P = 0.0169);
MVP
0.78
MPC
0.44
ClinPred
0.55
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-67250655; API