rs148986773

Variant names:

• chr11-67490896-C-T
• rs148986773
• NM_003977.4:c.896C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-67490896-C-T
• chr11-67490896-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003977.4(AIP):​c.896C>T​(p.Ala299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,612,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. A299T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: AIP NM_003977.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 0.0400
• Publications: 18 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061604917).
• BP6: Variant 11-67490896-C-T is Benign according to our data. Variant chr11-67490896-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41214.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00065 (99/152264) while in subpopulation AMR AF = 0.00105 (16/15304). AF 95% confidence interval is 0.000755. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 99 AD,Unknown gene.

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.896C>T	p.Ala299Val	missense	Exon 6 of 6	NP_003968.3	O00170
	AIP	NM_001302959.2		c.719C>T	p.Ala240Val	missense	Exon 6 of 6	NP_001289888.1	A0A804HKL7
	AIP	NM_001302960.2		c.*36C>T		3_prime_UTR	Exon 6 of 6	NP_001289889.1	A0A804HJ38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AIP	ENST00000279146.8	TSL:1 MANE Select	c.896C>T	p.Ala299Val	missense	Exon 6 of 6	ENSP00000279146.3	O00170
	AIP	ENST00000934218.1		c.986C>T	p.Ala329Val	missense	Exon 6 of 6	ENSP00000604277.1
	AIP	ENST00000872352.1		c.890C>T	p.Ala297Val	missense	Exon 6 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.000941

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000561 AC: 139 AN: 247974 AF XY: 0.000511

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000928 AC: 1355 AN: 1460360 Hom.: 1 Cov.: 32 AF XY: 0.000907 AC XY: 659 AN XY: 726468

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000604 AC: 27 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86232

European-Finnish (FIN) AF: 0.0000384 AC: 2 AN: 52086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00114 AC: 1267 AN: 1111930

Other (OTH) AF: 0.000828 AC: 50 AN: 60364

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74438

African (AFR) AF: 0.000409 AC: 17 AN: 41554

American (AMR) AF: 0.00105 AC: 16 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000868 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000455 AC: 55

EpiCase AF: 0.000763

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	AIP-related disorder (1)
-	-	1	Familial isolated pituitary adenoma (1)
-	-	1	Somatotroph adenoma (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.062	T
MetaSVM	Uncertain	0.056	D
PhyloP100		0.040
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.24	T
Vest4		0.13
MVP		0.72
MPC		0.38
ClinPred		0.014	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.56
Mutation Taster		=81/19	polymorphism

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: rs148986773; hg19: chr11-67258367;