18-26862297-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.56

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)

ACMG classification

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	UniProt
AQP4	NM_001650.7	c.332G>C	p.Ser111Thr	missense_variant	2/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.332G>C	p.Ser111Thr	missense_variant	2/5	1	NM_001650.7	P1

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

Submissions by phenotype

Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital

Nov 01, 2017

Case 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

Other links and lift over

dbSNP: rs1555661648; hg19: chr18-24442261;