18-26865883-G-T

Variant names:

• chr18-26865883-G-T
• rs162007
• ENST00000578701.5:n.54+523G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000578701.5(AQP4-AS1):​n.54+523G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 462,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: AQP4-AS1 ENST00000578701.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.627
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000578701.5. 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-AS1	NR_026908.1		n.53+523G>T		intron	N/A
	AQP4	NM_001650.7	MANE Select	c.-194C>A		upstream_gene	N/A	NP_001641.1
	AQP4	NM_001317384.3		c.-194C>A		upstream_gene	N/A	NP_001304313.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4-AS1	ENST00000578701.5	TSL:1	n.54+523G>T		intron	N/A
	AQP4-AS1	ENST00000568797.3	TSL:2	n.53+523G>T		intron	N/A
	AQP4-AS1	ENST00000579964.6	TSL:5	n.93-58877G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000216 AC: 1 AN: 462956 Hom.: 0 AF XY: 0.00000409 AC XY: 1 AN XY: 244592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12602

American (AMR) AF: 0.00 AC: 0 AN: 18960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15070

East Asian (EAS) AF: 0.00 AC: 0 AN: 30914

South Asian (SAS) AF: 0.0000221 AC: 1 AN: 45298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 280112

Other (OTH) AF: 0.00 AC: 0 AN: 26282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.78
PhyloP100		0.63
PromoterAI		-0.069	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs162007; hg19: chr18-24445847;