rs455671

Variant names:

• chr18-26862092-A-G
• rs455671
• NM_001650.7:c.447+90T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	NM_001650.7	MANE Select	c.447+90T>C		intron	N/A	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.447+90T>C		intron	N/A	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.381+90T>C		intron	N/A	NP_001351216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	ENST00000383168.9	TSL:1 MANE Select	c.447+90T>C		intron	N/A	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.381+90T>C		intron	N/A	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.447+90T>C		intron	N/A	ENSP00000500598.2	A0A5F9ZHR4

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

African (AFR) AF: 0.0614 AC: 1833 AN: 29844

American (AMR) AF: 0.125 AC: 5536 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 5886 AN: 25056

East Asian (EAS) AF: 0.387 AC: 15054 AN: 38864

South Asian (SAS) AF: 0.328 AC: 26876 AN: 81938

European-Finnish (FIN) AF: 0.162 AC: 8464 AN: 52264

Middle Eastern (MID) AF: 0.190 AC: 969 AN: 5094

European-Non Finnish (NFE) AF: 0.188 AC: 179117 AN: 954484

Other (OTH) AF: 0.197 AC: 10772 AN: 54742

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

African (AFR) AF: 0.0660 AC: 2743 AN: 41546

American (AMR) AF: 0.134 AC: 2058 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3468

East Asian (EAS) AF: 0.389 AC: 2008 AN: 5158

South Asian (SAS) AF: 0.331 AC: 1593 AN: 4814

European-Finnish (FIN) AF: 0.156 AC: 1647 AN: 10588

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13131 AN: 67988

Other (OTH) AF: 0.170 AC: 360 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.81
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs455671; hg19: chr18-24442056; COSMIC: COSV67219389; COSMIC: COSV67219389;