18-26856264-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001650.7(AQP4):c.919G>A(p.Gly307Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3367637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.919G>A	p.Gly307Arg	missense_variant	5/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.919G>A	p.Gly307Arg	missense_variant	5/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

The c.919G>A (p.G307R) alteration is located in exon 5 (coding exon 5) of the AQP4 gene. This alteration results from a G to A substitution at nucleotide position 919, causing the glycine (G) at amino acid position 307 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	0.57	D;D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.36	B;.;.
Vest4		0.30
MutPred		0.23		Loss of sheet (P = 0.0228);.;.;
MVP		0.92
MPC		0.20
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.23
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2054839331; hg19: chr18-24436228; COSMIC: COSV104701606; COSMIC: COSV104701606;