dbSNP rs104894190: AIP:p.Arg304Gln (chr11-67490911-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003977.4(AIP):c.911G>A(p.Arg304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,612,586 control chromosomes in the GnomAD database, including 4 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).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

AIP
NM_003977.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:7O:2

Conservation

PhyloP100: 3.41

Publications

38 publications found

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]

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

AIP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008575559).

BP6

Variant 11-67490911-G-A is Benign according to our data. Variant chr11-67490911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4893.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00108 (165/152354) while in subpopulation NFE AF = 0.00119 (81/68032). AF 95% confidence interval is 0.000981. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 165 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIP	NM_003977.4	MANE Select	c.911G>A	p.Arg304Gln	missense	Exon 6 of 6	NP_003968.3	O00170
AIP	NM_001302959.2		c.734G>A	p.Arg245Gln	missense	Exon 6 of 6	NP_001289888.1	A0A804HKL7
AIP	NM_001302960.2		c.*51G>A		3_prime_UTR	Exon 6 of 6	NP_001289889.1	A0A804HJ38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AIP	ENST00000279146.8	TSL:1 MANE Select	c.911G>A	p.Arg304Gln	missense	Exon 6 of 6	ENSP00000279146.3	O00170
AIP	ENST00000934218.1		c.1001G>A	p.Arg334Gln	missense	Exon 6 of 6	ENSP00000604277.1
AIP	ENST00000872352.1		c.905G>A	p.Arg302Gln	missense	Exon 6 of 6	ENSP00000542411.1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

165

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00165

AC:

409

AN:

247298

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.0000635

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.00116

AC:

1687

AN:

1460232

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

850

AN XY:

726406

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33476

American (AMR)

AF:

0.000716

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

484

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000384

AC:

AN:

52056

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000939

AC:

1044

AN:

1111874

Other (OTH)

AF:

0.00194

AC:

117

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

110

220

330

440

550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152354

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41582

American (AMR)

AF:

0.000392

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00107

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00141

AC:

170

EpiCase

AF:

0.00218

EpiControl

AF:

0.00148

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Somatotroph adenoma (5)

Hereditary cancer-predisposing syndrome (3)

AIP-related disorder (1)

not specified (1)

Dopamine agonists response (1)

Pituitary dependent hypercortisolism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.78

M_CAP

Benign

0.079

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.69

PhyloP100

3.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0090

Vest4

0.72

MVP

0.90

MPC

0.41

ClinPred

0.028

GERP RS

2.5

gMVP

0.57

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over