chr18-26862297-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001650.7(AQP4):​c.332G>C​(p.Ser111Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

AQP4
NM_001650.7 missense

Scores

6
7
6

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.56
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)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a modified_residue Phosphoserine; by PKG (size 0) in uniprot entity AQP4_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
Variant 18-26862297-C-G is Pathogenic according to our data. Variant chr18-26862297-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446492.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AQP4NM_001650.7 linkuse as main transcriptc.332G>C p.Ser111Thr missense_variant 2/5 ENST00000383168.9 NP_001641.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AQP4ENST00000383168.9 linkuse as main transcriptc.332G>C p.Ser111Thr missense_variant 2/51 NM_001650.7 ENSP00000372654 P1P55087-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Intellectual disability Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingCenter for Medical Genetics and Molecular Medicine, Haukeland University HospitalNov 01, 2017Case report accepted by Molecular Case Studies -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;.;.;D
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;.;D;D
M_CAP
Benign
0.065
D
MetaRNN
Pathogenic
0.93
D;D;D;D
MetaSVM
Uncertain
0.32
D
MutationAssessor
Benign
1.6
L;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-2.3
N;.;.;.
REVEL
Pathogenic
0.68
Sift
Uncertain
0.021
D;.;.;.
Sift4G
Benign
0.090
T;T;T;.
Polyphen
0.33
B;.;.;.
Vest4
0.74
MutPred
0.84
Gain of methylation at K109 (P = 0.114);.;.;.;
MVP
0.97
MPC
0.13
ClinPred
0.97
D
GERP RS
5.6
Varity_R
0.70
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1555661648; hg19: chr18-24442261; API