rs267606548

Variant names:

• chr11-67489295-A-G
• rs267606548
• NM_003977.4:c.308A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003977.4(AIP):​c.308A>G​(p.Lys103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 3.36

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25871694).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AIP	NM_003977.4	c.308A>G	p.Lys103Arg	missense_variant	Exon 3 of 6	ENST00000279146.8	NP_003968.3
AIP	NM_001302960.2	c.308A>G	p.Lys103Arg	missense_variant	Exon 3 of 6		NP_001289889.1
AIP	NM_001302959.2	c.131A>G	p.Lys44Arg	missense_variant	Exon 3 of 6		NP_001289888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AIP	ENST00000279146.8	c.308A>G	p.Lys103Arg	missense_variant	Exon 3 of 6	1	NM_003977.4	ENSP00000279146.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 247876 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459428 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	Published functional studies are conflicting (Igreja 2010, Bolger 2016, Formosa 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30764022, 21348957, 21512261, 23371967, 20457215, 25614825, 27267386, 28255869, 20507346, 20506337) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2025	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 103 of the AIP protein (p.Lys103Arg). This variant is present in population databases (rs267606548, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of AIP-related conditions (PMID: 20507346, 36149413). ClinVar contains an entry for this variant (Variation ID: 41174). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AIP function (PMID: 20506337, 28255869). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Somatotroph adenoma Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2024

The p.K103R variant (also known as c.308A>G), located in coding exon 3 of the AIP gene, results from an A to G substitution at nucleotide position 308. The lysine at codon 103 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Familial Isolated Pituitary Adenomas (FIPA) (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60; Stratakis CA et al. Clin. Genet. 2010 Nov;78:457-63; Guaraldi F et al. Clin Transl Sci. 2011 Feb;4:55-62; Beckers A et al. Endocr. Rev. 2013 Apr;34:239-77; Dinesen PT et al. Endocrinol Diabetes Metab Case Rep. 2015 Jan;2015:140105). Further, functional analysis using a yeast two-hybrid quantitative b-galactosidase assay assessed the interaction of AIP with PDE4A5, an AIP binding protein, and found that this alteration results in b-galactosidase assay activity values more than fivefold different from wild type suggesting that it leads to a complete loss of PDE4A5–AIP binding (Igreja S et al. Hum. Mutat. 2010 Aug;31:950-60). However another functional analysis using protein expression of the PDE4A5 rat homologue PDE4A4, suggests the p.K103R alteration has no clear inhibitory effect (Bolger GB et al. Endocr. Relat. Cancer, 2016 May;23:419-31). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.057	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
Vest4		0.28
MutPred		0.48		Loss of methylation at K103 (P = 0.06);
MVP		0.94
MPC		0.30
ClinPred		0.35	T
GERP RS		4.9
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267606548; hg19: chr11-67256766;