18-26861191-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001650.7(AQP4):c.552T>A(p.Asp184Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,614,164 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0088 (17 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (21 hom.)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007751614).
• BP6: Variant 18-26861191-A-T is Benign according to our data. Variant chr18-26861191-A-T is described in ClinVar as [Benign]. Clinvar id is 775395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00879 (1339/152320) while in subpopulation AFR AF= 0.0301 (1250/41568). AF 95% confidence interval is 0.0287. There are 17 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.552T>A	p.Asp184Glu	missense_variant	3/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.552T>A	p.Asp184Glu	missense_variant	3/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1338 AN: 152202 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00231 AC: 580 AN: 251446 Hom.: 9 AF XY: 0.00181 AC XY: 246 AN XY: 135896

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000839 AC: 1227 AN: 1461844 Hom.: 21 Cov.: 31 AF XY: 0.000748 AC XY: 544 AN XY: 727218

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00879 AC: 1339 AN: 152320 Hom.: 17 Cov.: 33 AF XY: 0.00791 AC XY: 589 AN XY: 74496

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.000382 Hom.: 1

Bravo AF: 0.0101

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00286 AC: 347

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;D
Eigen	Benign	-0.070
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T;.;T;T
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.090	T;.;.;.
Sift4G	Benign	0.11	T;T;T;.
Polyphen		0.20	B;.;.;.
Vest4		0.60
MutPred		0.44		Gain of ubiquitination at K181 (P = 0.0985);.;.;.;
MVP		0.92
MPC		0.17
ClinPred		0.023	T
GERP RS		4.5
Varity_R		0.48
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61731038; hg19: chr18-24441155;