18-26862428-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001650.7(AQP4):c.201G>T(p.Pro67=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,614,072 control chromosomes in the GnomAD database, including 11,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.087 (810 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10275 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.47

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 18-26862428-C-A is Benign according to our data. Variant chr18-26862428-C-A is described in ClinVar as [Benign]. Clinvar id is 3060164.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.201G>T	p.Pro67=	synonymous_variant	2/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.201G>T	p.Pro67=	synonymous_variant	2/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13286 AN: 152070 Hom.: 810 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0943

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0941

GnomAD3 exomes AF: 0.0896 AC: 22519 AN: 251424 Hom.: 1317 AF XY: 0.0899 AC XY: 12216 AN XY: 135908

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0673

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.112 AC: 163222 AN: 1461884 Hom.: 10275 Cov.: 32 AF XY: 0.110 AC XY: 79750 AN XY: 727246

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.0682

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0296

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0873 AC: 13284 AN: 152188 Hom.: 810 Cov.: 32 AF XY: 0.0873 AC XY: 6490 AN XY: 74380

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0942

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0931

Alfa AF: 0.105 Hom.: 436

Bravo AF: 0.0802

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AQP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.036
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35248760; hg19: chr18-24442392;