chr18-26856228-C-T

Variant names:

• chr18-26856228-C-T
• rs200498749
• NM_001650.7:c.955G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001650.7(AQP4):​c.955G>A​(p.Val319Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000402 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: AQP4 NM_001650.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34
• Publications: 4 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01529479).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001650.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	NM_001650.7	MANE Select	c.955G>A	p.Val319Ile	missense	Exon 5 of 5	NP_001641.1	F1DSG4
	AQP4	NM_001317384.3		c.955G>A	p.Val319Ile	missense	Exon 5 of 5	NP_001304313.1	A0A5F9ZHR4
	AQP4	NM_001364287.1		c.889G>A	p.Val297Ile	missense	Exon 5 of 5	NP_001351216.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP4	ENST00000383168.9	TSL:1 MANE Select	c.955G>A	p.Val319Ile	missense	Exon 5 of 5	ENSP00000372654.4	P55087-1
	AQP4	ENST00000581374.5	TSL:1	c.889G>A	p.Val297Ile	missense	Exon 4 of 4	ENSP00000462597.1	P55087-2
	AQP4	ENST00000672981.2		c.955G>A	p.Val319Ile	missense	Exon 5 of 5	ENSP00000500598.2	A0A5F9ZHR4

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000636 AC: 160 AN: 251484 AF XY: 0.000677

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000389 AC: 569 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000400 AC XY: 291 AN XY: 727244

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00316 AC: 169 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000329 AC: 366 AN: 1112008

Other (OTH) AF: 0.000513 AC: 31 AN: 60396

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000564 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.081
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.37
Sift	Benign	0.093	T
Sift4G	Benign	0.13	T
Polyphen		0.13	B
Vest4		0.38
MVP		0.77
MPC		0.10
ClinPred		0.041	T
GERP RS		5.8
Varity_R		0.070
gMVP		0.37
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200498749; hg19: chr18-24436192;