18-26856364-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001650.7(AQP4):c.819A>G(p.Thr273=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,614,262 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (33 hom.)
• Consequence: AQP4 NM_001650.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.69

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 18-26856364-T-C is Benign according to our data. Variant chr18-26856364-T-C is described in ClinVar as [Benign]. Clinvar id is 790431.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.69 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP4	NM_001650.7	c.819A>G	p.Thr273=	synonymous_variant	5/5	ENST00000383168.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP4	ENST00000383168.9	c.819A>G	p.Thr273=	synonymous_variant	5/5	1	NM_001650.7	P1

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00333 AC: 837 AN: 251486 Hom.: 4 AF XY: 0.00380 AC XY: 516 AN XY: 135920

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00901

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00519 AC: 7594 AN: 1461894 Hom.: 33 Cov.: 31 AF XY: 0.00535 AC XY: 3888 AN XY: 727248

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00885

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.00576

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.00309 AC XY: 230 AN XY: 74520

Gnomad4 AFR AF: 0.000962

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00316 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.00375 AC: 13 AN: 3478

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

Dec 04, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.093
Dann	Benign	0.67

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: rs72557972; hg19: chr18-24436328;