rs455671

Positions:

• chr18-26862092-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001650.7(AQP4):​c.447+90T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,438,840 control chromosomes in the GnomAD database, including 29,775 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 0.16 (2426 hom., cov: 32)
  • Exomes 𝑓: 0.20 (27349 hom.)
• Consequence: AQP4 NM_001650.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AQP4	NM_001650.7	c.447+90T>C		intron_variant		ENST00000383168.9	NP_001641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AQP4	ENST00000383168.9	c.447+90T>C		intron_variant		1	NM_001650.7	ENSP00000372654	P1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24636 AN: 152066 Hom.: 2428 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.198 AC: 254507 AN: 1286656 Hom.: 27349 Cov.: 20 AF XY: 0.203 AC XY: 131510 AN XY: 648796

Gnomad4 AFR exome AF: 0.0614

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.387

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.162 AC: 24645 AN: 152184 Hom.: 2426 Cov.: 32 AF XY: 0.165 AC XY: 12287 AN XY: 74388

Gnomad4 AFR AF: 0.0660

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.389

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.170

Alfa AF: 0.157 Hom.: 294

Bravo AF: 0.150

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs455671; hg19: chr18-24442056; COSMIC: COSV67219389; COSMIC: COSV67219389;