15-58184082-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020980.5(AQP9):c.835A>G(p.Thr279Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,613,952 control chromosomes in the GnomAD database, including 715,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.90 ( 61949 hom., cov: 30)

Exomes 𝑓: 0.94 ( 653580 hom. )

Consequence

AQP9
NM_020980.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0540

Publications

34 publications found

Variant links:

Genes affected

AQP9 (HGNC:643): (aquaporin 9) The aquaporins are a family of water-selective membrane channels. This gene encodes a member of a subset of aquaporins called the aquaglyceroporins. This protein allows passage of a broad range of noncharged solutes and also stimulates urea transport and osmotic water permeability. This protein may also facilitate the uptake of glycerol in hepatic tissue . The encoded protein may also play a role in specialized leukocyte functions such as immunological response and bactericidal activity. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

AQP9 links:

ALDH1A2 (HGNC:15472): (aldehyde dehydrogenase 1 family member A2) This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011]

ALDH1A2 Gene-Disease associations (from GenCC):

diaphragmatic hernia 4, with cardiovascular defects
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ALDH1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.974237E-7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP9	NM_020980.5 link	c.835A>G	p.Thr279Ala	missense_variant	Exon 6 of 6	ENST00000219919.9	NP_066190.2	O43315
AQP9	NM_001320636.1 link	c.640A>G	p.Thr214Ala	missense_variant	Exon 6 of 6		NP_001307565.1	H0YK62
AQP9	NM_001320635.2 link	c.*35A>G		3_prime_UTR_variant	Exon 5 of 5		NP_001307564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP9	ENST00000219919.9 link	c.835A>G	p.Thr279Ala	missense_variant	Exon 6 of 6	1	NM_020980.5	ENSP00000219919.4		O43315

Frequencies

GnomAD3 genomes

AF:

0.899

AC:

136647

AN:

152026

Hom.:

61913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.781

Gnomad AMI

AF:

0.973

Gnomad AMR

AF:

0.926

Gnomad ASJ

AF:

0.963

Gnomad EAS

AF:

0.828

Gnomad SAS

AF:

0.870

Gnomad FIN

AF:

0.942

Gnomad MID

AF:

0.918

Gnomad NFE

AF:

0.960

Gnomad OTH

AF:

0.915

GnomAD2 exomes

AF:

0.919

AC:

231148

AN:

251388

AF XY:

0.921

show subpopulations

Gnomad AFR exome

AF:

0.778

Gnomad AMR exome

AF:

0.919

Gnomad ASJ exome

AF:

0.967

Gnomad EAS exome

AF:

0.841

Gnomad FIN exome

AF:

0.943

Gnomad NFE exome

AF:

0.956

Gnomad OTH exome

AF:

0.941

GnomAD4 exome

AF:

0.945

AC:

1381081

AN:

1461808

Hom.:

653580

Cov.:

AF XY:

0.943

AC XY:

685864

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.779

AC:

26090

AN:

33480

American (AMR)

AF:

0.919

AC:

41117

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.966

AC:

25256

AN:

26136

East Asian (EAS)

AF:

0.853

AC:

33853

AN:

39698

South Asian (SAS)

AF:

0.873

AC:

75331

AN:

86254

European-Finnish (FIN)

AF:

0.942

AC:

50325

AN:

53420

Middle Eastern (MID)

AF:

0.908

AC:

5239

AN:

5768

European-Non Finnish (NFE)

AF:

0.960

AC:

1067580

AN:

1111940

Other (OTH)

AF:

0.932

AC:

56290

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4025

8050

12074

16099

20124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21610

43220

64830

86440

108050

<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:

0.899

AC:

136740

AN:

152144

Hom.:

61949

Cov.:

AF XY:

0.897

AC XY:

66750

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.781

AC:

32369

AN:

41446

American (AMR)

AF:

0.926

AC:

14171

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

3345

AN:

3472

East Asian (EAS)

AF:

0.828

AC:

4276

AN:

5162

South Asian (SAS)

AF:

0.870

AC:

4200

AN:

4826

European-Finnish (FIN)

AF:

0.942

AC:

9984

AN:

10598

Middle Eastern (MID)

AF:

0.918

AC:

270

AN:

294

European-Non Finnish (NFE)

AF:

0.960

AC:

65305

AN:

68022

Other (OTH)

AF:

0.916

AC:

1935

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

653

1305

1958

2610

3263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.939

Hom.:

280363

Bravo

AF:

0.894

TwinsUK

AF:

0.960

AC:

3558

ALSPAC

AF:

0.957

AC:

3687

ESP6500AA

AF:

0.790

AC:

3462

ESP6500EA

AF:

0.957

AC:

8217

ExAC

AF:

0.915

AC:

111059

Asia WGS

AF:

0.836

AC:

2907

AN:

3478

EpiCase

AF:

0.959

EpiControl

AF:

0.956

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.47

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.020

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.12

T;.;T

MetaRNN

Benign

8.0e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

.;N;N

PhyloP100

0.054

PrimateAI

Benign

0.25

PROVEAN

Benign

0.080

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.86

T;T;T

Sift4G

Benign

0.87

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.014

MPC

0.010

ClinPred

0.010

GERP RS

-3.7

Varity_R

0.027

gMVP

0.58

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over