rs3875089

Variant names:

• chr18-26865469-T-C
• rs3875089
• NM_001650.7:c.32+189A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001650.7(AQP4):​c.32+189A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 740,602 control chromosomes in the GnomAD database, including 9,993 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 0.19 (3071 hom., cov: 32)
  • Exomes 𝑓: 0.14 (6922 hom.)
• Consequence: AQP4 NM_001650.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 17 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	NM_001650.7	MANE Select	c.32+189A>G		intron	N/A	NP_001641.1
	AQP4	NM_001317384.3		c.32+189A>G		intron	N/A	NP_001304313.1
	AQP4	NM_001364287.1		c.-35+189A>G		intron	N/A	NP_001351216.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	ENST00000383168.9	TSL:1 MANE Select	c.32+189A>G		intron	N/A	ENSP00000372654.4
	AQP4-AS1	ENST00000578701.5	TSL:1	n.54+109T>C		intron	N/A
	AQP4	ENST00000672981.2		c.32+189A>G		intron	N/A	ENSP00000500598.2

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28230 AN: 152016 Hom.: 3054 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.144 AC: 84653 AN: 588468 Hom.: 6922 Cov.: 7 AF XY: 0.143 AC XY: 45026 AN XY: 315858

African (AFR) AF: 0.294 AC: 4801 AN: 16306

American (AMR) AF: 0.0936 AC: 3168 AN: 33844

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2699 AN: 18626

East Asian (EAS) AF: 0.00168 AC: 58 AN: 34490

South Asian (SAS) AF: 0.130 AC: 8005 AN: 61444

European-Finnish (FIN) AF: 0.190 AC: 7155 AN: 37582

Middle Eastern (MID) AF: 0.123 AC: 479 AN: 3898

European-Non Finnish (NFE) AF: 0.153 AC: 53591 AN: 350872

Other (OTH) AF: 0.150 AC: 4697 AN: 31406

GnomAD4 genome AF: 0.186 AC: 28290 AN: 152134 Hom.: 3071 Cov.: 32 AF XY: 0.185 AC XY: 13793 AN XY: 74358

African (AFR) AF: 0.291 AC: 12062 AN: 41478

American (AMR) AF: 0.136 AC: 2086 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 498 AN: 3470

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.127 AC: 612 AN: 4822

European-Finnish (FIN) AF: 0.207 AC: 2183 AN: 10570

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10298 AN: 68000

Other (OTH) AF: 0.160 AC: 339 AN: 2114

Alfa AF: 0.166 Hom.: 5169

Bravo AF: 0.184

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.90
PhyloP100		1.4
PromoterAI		0.013	Neutral
Mutation Taster		=99/1	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: rs3875089; hg19: chr18-24445433;