Genetic Variant AQP4:c.32+189A>G (chr18-26865469-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001650.7(AQP4):c.32+189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 740,602 control chromosomes in the GnomAD database, including 9,993 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 0.19 ( 3071 hom., cov: 32)

Exomes 𝑓: 0.14 ( 6922 hom. )

Consequence

AQP4
NM_001650.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

Publications

17 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP4	NM_001650.7 link	c.32+189A>G		intron_variant	Intron 1 of 4	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.32+189A>G		intron_variant	Intron 1 of 4	1	NM_001650.7	ENSP00000372654.4		P55087-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28230

AN:

152016

Hom.:

3054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.165

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.00443

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.163

GnomAD4 exome

AF:

0.144

AC:

84653

AN:

588468

Hom.:

6922

Cov.:

AF XY:

0.143

AC XY:

45026

AN XY:

315858

show subpopulations

African (AFR)

AF:

0.294

AC:

4801

AN:

16306

American (AMR)

AF:

0.0936

AC:

3168

AN:

33844

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

2699

AN:

18626

East Asian (EAS)

AF:

0.00168

AC:

AN:

34490

South Asian (SAS)

AF:

0.130

AC:

8005

AN:

61444

European-Finnish (FIN)

AF:

0.190

AC:

7155

AN:

37582

Middle Eastern (MID)

AF:

0.123

AC:

479

AN:

3898

European-Non Finnish (NFE)

AF:

0.153

AC:

53591

AN:

350872

Other (OTH)

AF:

0.150

AC:

4697

AN:

31406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

3654

7308

10961

14615

18269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.186

AC:

28290

AN:

152134

Hom.:

3071

Cov.:

AF XY:

0.185

AC XY:

13793

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.291

AC:

12062

AN:

41478

American (AMR)

AF:

0.136

AC:

2086

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

498

AN:

3470

East Asian (EAS)

AF:

0.00444

AC:

AN:

5180

South Asian (SAS)

AF:

0.127

AC:

612

AN:

4822

European-Finnish (FIN)

AF:

0.207

AC:

2183

AN:

10570

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.151

AC:

10298

AN:

68000

Other (OTH)

AF:

0.160

AC:

339

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1116

2232

3347

4463

5579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.166

Hom.:

5169

Bravo

AF:

0.184

Asia WGS

AF:

0.0790

AC:

276

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.4

PromoterAI

0.013

Neutral

(source)

Mutation Taster

=99/1

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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chr18-26865469-T-C

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