18-26862246-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001650.7(AQP4):c.383T>C(p.Ile128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,614,124 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (7 hom.)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009894133).
• BP6: Variant 18-26862246-A-G is Benign according to our data. Variant chr18-26862246-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3055334.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.383T>C	p.Ile128Thr	missense_variant	2/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.383T>C	p.Ile128Thr	missense_variant	2/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00135 AC: 340 AN: 251386 Hom.: 3 AF XY: 0.00132 AC XY: 180 AN XY: 135900

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00399

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000629 AC: 920 AN: 1461878 Hom.: 7 Cov.: 30 AF XY: 0.000679 AC XY: 494 AN XY: 727240

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74438

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000519 Hom.: 0

Bravo AF: 0.00352

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00156 AC: 189

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AQP4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 28, 2020

This variant is classified as likely 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
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	14
Dann	Benign	0.92
DEOGEN2	Uncertain	0.42	T;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.69	T;.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.43	N;.;.;.
MutationTaster	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.13	N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;.;.;.
Sift4G	Benign	0.20	T;T;T;.
Polyphen		0.0040	B;.;.;.
Vest4		0.27
MVP		0.79
MPC		0.16
ClinPred		0.0028	T
GERP RS		4.4
Varity_R		0.067
gMVP		0.51

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: rs61731042; hg19: chr18-24442210;