Genetic Variant AQP4:c.*357G>A (chr18-26855854-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001650.7(AQP4):c.*357G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 303,576 control chromosomes in the GnomAD database, including 15,445 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7603 hom., cov: 32)

Exomes 𝑓: 0.32 ( 7842 hom. )

Consequence

AQP4
NM_001650.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.382

Publications

30 publications found

Variant links:

Genes affected

AQP4 (HGNC:637): (aquaporin 4) This gene encodes a member of the aquaporin family of intrinsic membrane proteins that function as water-selective channels in the plasma membranes of many cells. This protein is the predominant aquaporin found in brain and has an important role in brain water homeostasis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. Additional isoforms, resulting from the use of alternative in-frame translation initiation codons, have also been described. Recent studies provided evidence for translational readthrough in this gene, and expression of C-terminally extended isoforms via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]

AQP4 links:

AQP4-AS1 (HGNC:26399): (AQP4 antisense RNA 1)

AQP4-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP4	NM_001650.7 link	c.*357G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000383168.9	NP_001641.1	P55087-1F1DSG4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP4	ENST00000383168.9 link	c.*357G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_001650.7	ENSP00000372654.4		P55087-1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46544

AN:

151754

Hom.:

7583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.235

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.411

Gnomad SAS

AF:

0.257

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.312

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.331

GnomAD4 exome

AF:

0.316

AC:

47872

AN:

151704

Hom.:

7842

Cov.:

AF XY:

0.309

AC XY:

25165

AN XY:

81498

show subpopulations

African (AFR)

AF:

0.238

AC:

1020

AN:

4284

American (AMR)

AF:

0.481

AC:

2806

AN:

5834

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1148

AN:

3916

East Asian (EAS)

AF:

0.408

AC:

2683

AN:

6574

South Asian (SAS)

AF:

0.260

AC:

6535

AN:

25174

European-Finnish (FIN)

AF:

0.282

AC:

2177

AN:

7710

Middle Eastern (MID)

AF:

0.303

AC:

177

AN:

584

European-Non Finnish (NFE)

AF:

0.321

AC:

28866

AN:

89960

Other (OTH)

AF:

0.321

AC:

2460

AN:

7668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1570

3141

4711

6282

7852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<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:

0.307

AC:

46605

AN:

151872

Hom.:

7603

Cov.:

AF XY:

0.306

AC XY:

22706

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.234

AC:

9706

AN:

41394

American (AMR)

AF:

0.459

AC:

7009

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

931

AN:

3466

East Asian (EAS)

AF:

0.411

AC:

2115

AN:

5140

South Asian (SAS)

AF:

0.258

AC:

1242

AN:

4808

European-Finnish (FIN)

AF:

0.259

AC:

2730

AN:

10534

Middle Eastern (MID)

AF:

0.312

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.321

AC:

21798

AN:

67952

Other (OTH)

AF:

0.338

AC:

713

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1595

3190

4786

6381

7976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.318

Hom.:

23981

Bravo

AF:

0.324

Asia WGS

AF:

0.346

AC:

1206

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.7

(source)

DANN

Benign

0.49

PhyloP100

0.38

Mutation Taster

=100/0

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