rs1063385

chr11-67487051-G-Achr11-67487051-G-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.145G>A(p.Val49Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,944 control chromosomes in the GnomAD database, including 1 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. V49L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: 1.97

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 (MetaRNN=0.16382807).
• BP6: Variant 11-67487051-G-A is Benign according to our data. Variant chr11-67487051-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41164.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000854 (13/152216) while in subpopulation EAS AF= 0.000964 (5/5188). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AIP	NM_003977.4	c.145G>A	p.Val49Met	missense_variant	2/6	ENST00000279146.8
AIP	NM_001302960.2	c.145G>A	p.Val49Met	missense_variant	2/6
AIP	NM_001302959.2	c.-33G>A		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AIP	ENST00000279146.8	c.145G>A	p.Val49Met	missense_variant	2/6	1	NM_003977.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000964

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: 0.000275 AC: 69 AN: 251326 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461728 Hom.: 1 Cov.: 32 AF XY: 0.000143 AC XY: 104 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Somatotroph adenoma Uncertain:1 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 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 23, 2021	- -

AIP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	0.71	D
MutationTaster	Benign	0.96	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.0030	D;D
Vest4		0.24
MVP		0.96
MPC		0.44
ClinPred		0.13	T
GERP RS		3.3
gMVP		0.55

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: rs1063385; hg19: chr11-67254522; COSMIC: COSV54161251; COSMIC: COSV54161251;