chr18-26865728-C-T

Variant names:

• chr18-26865728-C-T
• rs162008
• ENST00000578701.5:n.54+368C>T

Variant summary

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

The NM_001364287.1(AQP4):​c.-105G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,612,618 control chromosomes in the GnomAD database, including 33,551 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 0.17 (2562 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30989 hom.)
• Consequence: AQP4 NM_001364287.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.391
• Publications: 18 publications found

Genes affected

AQP4-AS1 (HGNC:26399): (AQP4 antisense RNA 1)

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 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• megalencephalic leukoencephalopathy with subcortical cysts 4, remitting

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neuromyelitis optica

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364287.1. 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_001364287.1		c.-105G>A		5_prime_UTR	Exon 1 of 5	NP_001351216.1
	AQP4	NM_001364286.1		c.-105G>A		5_prime_UTR	Exon 1 of 5	NP_001351215.1	P55087-2
	AQP4-AS1	NR_026908.1		n.53+368C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4-AS1	ENST00000578701.5	TSL:1	n.54+368C>T		intron	N/A
	AQP4	ENST00000672188.1		c.-39G>A		5_prime_UTR	Exon 1 of 5	ENSP00000500720.1	P55087-1
	AQP4	ENST00000906982.1		c.-39G>A		5_prime_UTR	Exon 1 of 5	ENSP00000577041.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26476 AN: 152028 Hom.: 2568 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.204 AC: 51209 AN: 251046 AF XY: 0.212

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.201 AC: 293643 AN: 1460472 Hom.: 30989 Cov.: 32 AF XY: 0.204 AC XY: 148466 AN XY: 726634

African (AFR) AF: 0.0981 AC: 3283 AN: 33458

American (AMR) AF: 0.120 AC: 5351 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6335 AN: 26128

East Asian (EAS) AF: 0.364 AC: 14437 AN: 39694

South Asian (SAS) AF: 0.295 AC: 25401 AN: 86222

European-Finnish (FIN) AF: 0.171 AC: 9102 AN: 53384

Middle Eastern (MID) AF: 0.198 AC: 1143 AN: 5768

European-Non Finnish (NFE) AF: 0.195 AC: 216369 AN: 1110740

Other (OTH) AF: 0.203 AC: 12222 AN: 60354

GnomAD4 genome AF: 0.174 AC: 26458 AN: 152146 Hom.: 2562 Cov.: 33 AF XY: 0.176 AC XY: 13116 AN XY: 74378

African (AFR) AF: 0.101 AC: 4191 AN: 41516

American (AMR) AF: 0.142 AC: 2170 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 887 AN: 3472

East Asian (EAS) AF: 0.363 AC: 1873 AN: 5164

South Asian (SAS) AF: 0.297 AC: 1427 AN: 4812

European-Finnish (FIN) AF: 0.163 AC: 1725 AN: 10586

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13546 AN: 67986

Other (OTH) AF: 0.188 AC: 397 AN: 2108

Alfa AF: 0.169 Hom.: 1204

Bravo AF: 0.165

Asia WGS AF: 0.291 AC: 1011 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.89
PhyloP100		-0.39
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	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: rs162008; hg19: chr18-24445692; COSMIC: COSV67218390; COSMIC: COSV67218390;