Variant 18-26861191-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001650.7(AQP4):c.552T>A(p.Asp184Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,164 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0088 ( 17 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 21 hom. )

Consequence

AQP4
NM_001650.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.00

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007751614).

BP6

Variant 18-26861191-A-T is Benign according to our data. Variant chr18-26861191-A-T is described in ClinVar as [Benign]. Clinvar id is 775395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00879 (1339/152320) while in subpopulation AFR AF= 0.0301 (1250/41568). AF 95% confidence interval is 0.0287. There are 17 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7 linkuse as main transcript	c.552T>A	p.Asp184Glu	missense_variant	3/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9 linkuse as main transcript	c.552T>A	p.Asp184Glu	missense_variant	3/5	1	NM_001650.7	P1	P55087-1

Frequencies

GnomAD3 genomes

AF:

0.00879

AC:

1338

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00231

AC:

580

AN:

251446

Hom.:

AF XY:

0.00181

AC XY:

246

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000839

AC:

1227

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

544

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0289

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.00204

GnomAD4 genome

AF:

0.00879

AC:

1339

AN:

152320

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

589

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0301

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.000382

Hom.:

Bravo

AF:

0.0101

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00286

AC:

347

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

D;.;.;D

Eigen

Benign

-0.070

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;.;T;T

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.7

L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.8

D;.;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.090

T;.;.;.

Sift4G

Benign

0.11

T;T;T;.

Polyphen

0.20

B;.;.;.

Vest4

0.60

MutPred

0.44

Gain of ubiquitination at K181 (P = 0.0985);.;.;.;

MVP

0.92

MPC

0.17

ClinPred

0.023

GERP RS

4.5

Varity_R

0.48

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over