18-26855854-C-T

Variant names:

• chr18-26855854-C-T
• rs3763043
• NM_001650.7:c.*357G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001650.7(AQP4):​c.*357G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 303,576 control chromosomes in the GnomAD database, including 15,445 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 0.31 (7603 hom., cov: 32)
  • Exomes 𝑓: 0.32 (7842 hom.)
• Consequence: AQP4 NM_001650.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.382
• Publications: 30 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 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.*357G>A		3_prime_UTR	Exon 5 of 5	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.*270G>A		3_prime_UTR	Exon 5 of 5	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.*270G>A		3_prime_UTR	Exon 5 of 5	NP_001351216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	ENST00000383168.9	TSL:1 MANE Select	c.*357G>A		3_prime_UTR	Exon 5 of 5	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.*357G>A		3_prime_UTR	Exon 4 of 4	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.*270G>A		3_prime_UTR	Exon 5 of 5	ENSP00000500598.2	A0A5F9ZHR4

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46544 AN: 151754 Hom.: 7583 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.331

GnomAD4 exome AF: 0.316 AC: 47872 AN: 151704 Hom.: 7842 Cov.: 0 AF XY: 0.309 AC XY: 25165 AN XY: 81498

African (AFR) AF: 0.238 AC: 1020 AN: 4284

American (AMR) AF: 0.481 AC: 2806 AN: 5834

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1148 AN: 3916

East Asian (EAS) AF: 0.408 AC: 2683 AN: 6574

South Asian (SAS) AF: 0.260 AC: 6535 AN: 25174

European-Finnish (FIN) AF: 0.282 AC: 2177 AN: 7710

Middle Eastern (MID) AF: 0.303 AC: 177 AN: 584

European-Non Finnish (NFE) AF: 0.321 AC: 28866 AN: 89960

Other (OTH) AF: 0.321 AC: 2460 AN: 7668

GnomAD4 genome AF: 0.307 AC: 46605 AN: 151872 Hom.: 7603 Cov.: 32 AF XY: 0.306 AC XY: 22706 AN XY: 74190

African (AFR) AF: 0.234 AC: 9706 AN: 41394

American (AMR) AF: 0.459 AC: 7009 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 931 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2115 AN: 5140

South Asian (SAS) AF: 0.258 AC: 1242 AN: 4808

European-Finnish (FIN) AF: 0.259 AC: 2730 AN: 10534

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21798 AN: 67952

Other (OTH) AF: 0.338 AC: 713 AN: 2110

Alfa AF: 0.318 Hom.: 23981

Bravo AF: 0.324

Asia WGS AF: 0.346 AC: 1206 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.49
PhyloP100		0.38
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: rs3763043; hg19: chr18-24435818;