dbSNP rs1058424: AQP4:c.*630T>A (chr18-26855581-A-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.*630T>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 0.186 in 153,174 control chromosomes in the GnomAD database, including 3,238 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 ( 3228 hom., cov: 33)

Exomes 𝑓: 0.13 ( 10 hom. )

Consequence

AQP4
NM_001650.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.129

Publications

13 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=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001650.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AQP4	NM_001650.7	MANE Select	c.*630T>A	3_prime_UTR	Exon 5 of 5	NP_001641.1	F1DSG4
AQP4	NM_001317384.3		c.*543T>A	3_prime_UTR	Exon 5 of 5	NP_001304313.1	A0A5F9ZHR4
AQP4	NM_001364287.1		c.*543T>A	3_prime_UTR	Exon 5 of 5	NP_001351216.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AQP4	ENST00000383168.9	TSL:1 MANE Select	c.*630T>A	3_prime_UTR	Exon 5 of 5	ENSP00000372654.4	P55087-1
AQP4	ENST00000672981.2		c.*543T>A	3_prime_UTR	Exon 5 of 5	ENSP00000500598.2	A0A5F9ZHR4
AQP4	ENST00000672188.1		c.*630T>A	3_prime_UTR	Exon 5 of 5	ENSP00000500720.1	P55087-1

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28388

AN:

152030

Hom.:

3214

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0963

Gnomad AMI

AF:

0.194

Gnomad AMR

AF:

0.321

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.414

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.168

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.219

GnomAD4 exome

AF:

0.129

AC:

132

AN:

1026

Hom.:

Cov.:

AF XY:

0.130

AC XY:

AN XY:

584

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.121

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AF:

0.0625

AC:

AN:

European-Finnish (FIN)

AF:

0.178

AC:

AN:

394

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0957

AC:

AN:

512

Other (OTH)

AF:

0.111

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.187

AC:

28414

AN:

152148

Hom.:

3228

Cov.:

AF XY:

0.189

AC XY:

14025

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0960

AC:

3986

AN:

41528

American (AMR)

AF:

0.321

AC:

4907

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

643

AN:

3466

East Asian (EAS)

AF:

0.414

AC:

2143

AN:

5182

South Asian (SAS)

AF:

0.181

AC:

873

AN:

4818

European-Finnish (FIN)

AF:

0.168

AC:

1778

AN:

10584

Middle Eastern (MID)

AF:

0.226

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.197

AC:

13362

AN:

67976

Other (OTH)

AF:

0.227

AC:

479

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1141

2282

3422

4563

5704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.185

Hom.:

351

Bravo

AF:

0.197

Asia WGS

AF:

0.301

AC:

1049

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.64

(source)

DANN

Benign

0.79

PhyloP100

-0.13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over