Genetic Variant AQP4:p.Leu164Leu (chr18-26861251-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001650.7(AQP4):c.492G>A(p.Leu164Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,006 control chromosomes in the GnomAD database, including 799 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 0.025 ( 69 hom., cov: 33)

Exomes 𝑓: 0.023 ( 730 hom. )

Consequence

AQP4
NM_001650.7 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

6 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP7

Synonymous conserved (PhyloP=2.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP4	NM_001650.7 link	c.492G>A	p.Leu164Leu	synonymous_variant	Exon 3 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.492G>A	p.Leu164Leu	synonymous_variant	Exon 3 of 5	1	NM_001650.7	ENSP00000372654.4		P55087-1

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3753

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0330

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.0986

Gnomad FIN

AF:

0.0360

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0176

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0286

AC:

7180

AN:

251384

AF XY:

0.0329

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.00899

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.00234

Gnomad FIN exome

AF:

0.0365

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0232

AC:

33931

AN:

1461706

Hom.:

730

Cov.:

AF XY:

0.0255

AC XY:

18517

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.0344

AC:

1151

AN:

33474

American (AMR)

AF:

0.00903

AC:

404

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

579

AN:

26134

East Asian (EAS)

AF:

0.00169

AC:

AN:

39688

South Asian (SAS)

AF:

0.0946

AC:

8157

AN:

86254

European-Finnish (FIN)

AF:

0.0350

AC:

1870

AN:

53414

Middle Eastern (MID)

AF:

0.0368

AC:

212

AN:

5768

European-Non Finnish (NFE)

AF:

0.0182

AC:

20237

AN:

1111858

Other (OTH)

AF:

0.0208

AC:

1254

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1786

3571

5357

7142

8928

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.0246

AC:

3753

AN:

152300

Hom.:

Cov.:

AF XY:

0.0268

AC XY:

1993

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0330

AC:

1372

AN:

41566

American (AMR)

AF:

0.0124

AC:

190

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.00366

AC:

AN:

5186

South Asian (SAS)

AF:

0.0983

AC:

474

AN:

4822

European-Finnish (FIN)

AF:

0.0360

AC:

382

AN:

10620

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0176

AC:

1197

AN:

68012

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

190

379

569

758

948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0214

Hom.:

Bravo

AF:

0.0216

Asia WGS

AF:

0.0450

AC:

157

AN:

3478

EpiCase

AF:

0.0186

EpiControl

AF:

0.0175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

2.0

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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