Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_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

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.56

Publications

2 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: Uncertain_significance. The variant received 5 ACMG points.

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 VariationId is 446492.Status of the report is no_assertion_criteria_provided, 0 stars.

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	HGVSp	Effect	Exon Rank	Protein
AQP4	NM_001650.7	MANE Select	c.332G>C	p.Ser111Thr	missense	Exon 2 of 5	NP_001641.1
AQP4	NM_001317384.3		c.332G>C	p.Ser111Thr	missense	Exon 2 of 5	NP_001304313.1
AQP4	NM_001364287.1		c.266G>C	p.Ser89Thr	missense	Exon 2 of 5	NP_001351216.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP4	ENST00000383168.9	TSL:1 MANE Select	c.332G>C	p.Ser111Thr	missense	Exon 2 of 5	ENSP00000372654.4
AQP4	ENST00000581374.5	TSL:1	c.266G>C	p.Ser89Thr	missense	Exon 1 of 4	ENSP00000462597.1
AQP4	ENST00000672981.2		c.332G>C	p.Ser111Thr	missense	Exon 2 of 5	ENSP00000500598.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.6

PhyloP100

7.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.3

REVEL

Pathogenic

0.68

Sift

Uncertain

0.021

Sift4G

Benign

0.090

Polyphen

0.33

Vest4

0.74

MutPred

0.84

Gain of methylation at K109 (P = 0.114)

MVP

0.97

MPC

0.13

ClinPred

0.97

GERP RS

5.6

Varity_R

0.70

gMVP

0.72

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over