rs1839318

Positions:

• chr18-26861251-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001650.7(AQP4):​c.492G>A​(p.Leu164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,006 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (69 hom., cov: 33)
  • Exomes 𝑓: 0.023 (730 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.091 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.492G>A	p.Leu164=	synonymous_variant	3/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.492G>A	p.Leu164=	synonymous_variant	3/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3753 AN: 152182 Hom.: 70 Cov.: 33

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0986

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0286 AC: 7180 AN: 251384 Hom.: 215 AF XY: 0.0329 AC XY: 4468 AN XY: 135868

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00899

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.0989

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0181

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0232 AC: 33931 AN: 1461706 Hom.: 730 Cov.: 31 AF XY: 0.0255 AC XY: 18517 AN XY: 727160

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00903

Gnomad4 ASJ exome AF: 0.0222

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0946

Gnomad4 FIN exome AF: 0.0350

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0246 AC: 3753 AN: 152300 Hom.: 69 Cov.: 33 AF XY: 0.0268 AC XY: 1993 AN XY: 74468

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.0983

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0201 Hom.: 29

Bravo AF: 0.0216

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0186

EpiControl AF: 0.0175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1839318; hg19: chr18-24441215;