chr18-26861165-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_001650.7(AQP4):ā€‹c.578T>Cā€‹(p.Ile193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,614,138 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0023 ( 0 hom., cov: 33)
Exomes š‘“: 0.00021 ( 2 hom. )

Consequence

AQP4
NM_001650.7 missense

Scores

11
5
2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.95
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-AS1 (HGNC:26399): (AQP4 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.018962353).
BP6
Variant 18-26861165-A-G is Benign according to our data. Variant chr18-26861165-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 709494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AQP4NM_001650.7 linkuse as main transcriptc.578T>C p.Ile193Thr missense_variant 3/5 ENST00000383168.9 NP_001641.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AQP4ENST00000383168.9 linkuse as main transcriptc.578T>C p.Ile193Thr missense_variant 3/51 NM_001650.7 ENSP00000372654 P1P55087-1

Frequencies

GnomAD3 genomes
AF:
0.00225
AC:
342
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00808
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000521
AC:
131
AN:
251442
Hom.:
0
AF XY:
0.000361
AC XY:
49
AN XY:
135892
show subpopulations
Gnomad AFR exome
AF:
0.00794
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000210
AC:
307
AN:
1461838
Hom.:
2
Cov.:
31
AF XY:
0.000197
AC XY:
143
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00806
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.00226
AC:
344
AN:
152300
Hom.:
0
Cov.:
33
AF XY:
0.00213
AC XY:
159
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00811
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00103
Hom.:
0
Bravo
AF:
0.00229
ESP6500AA
AF:
0.00817
AC:
36
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000774
AC:
94
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 15, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;.;.;D
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D;D
MetaRNN
Benign
0.019
T;T;T;T
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.3
M;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-4.4
D;.;.;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
D;.;.;.
Vest4
0.93
MVP
0.99
MPC
0.65
ClinPred
0.16
T
GERP RS
5.6
Varity_R
0.80
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs61731037; hg19: chr18-24441129; API