rs267606581

Variant names:

• chr11-67490829-G-C
• rs267606581
• NM_003977.4:c.829G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003977.4(AIP):​c.829G>C​(p.Ala277Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A277V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.70
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• growth hormone secreting pituitary adenoma 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial isolated pituitary adenoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acromegaly

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003977.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIP	NM_003977.4	MANE Select	c.829G>C	p.Ala277Pro	missense	Exon 6 of 6	NP_003968.3	O00170
	AIP	NM_001302960.2		c.821G>C	p.Gly274Ala	missense	Exon 6 of 6	NP_001289889.1	A0A804HJ38
	AIP	NM_001302959.2		c.652G>C	p.Ala218Pro	missense	Exon 6 of 6	NP_001289888.1	A0A804HKL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIP	ENST00000279146.8	TSL:1 MANE Select	c.829G>C	p.Ala277Pro	missense	Exon 6 of 6	ENSP00000279146.3	O00170
	AIP	ENST00000934218.1		c.919G>C	p.Ala307Pro	missense	Exon 6 of 6	ENSP00000604277.1
	AIP	ENST00000872352.1		c.823G>C	p.Ala275Pro	missense	Exon 6 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	-	-	Somatotroph adenoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.22	D
PhyloP100		7.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.60
Sift	Benign	0.051	T
Sift4G	Benign	0.082	T
Vest4		0.77
MutPred		0.57		Loss of MoRF binding (P = 0.0604)
MVP		0.70
MPC		1.3
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.90
Mutation Taster		=24/76	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606581; hg19: chr11-67258300;