chr18-26856371-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001650.7(AQP4):ā€‹c.812A>Gā€‹(p.Gln271Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

AQP4
NM_001650.7 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16695982).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AQP4NM_001650.7 linkuse as main transcriptc.812A>G p.Gln271Arg missense_variant 5/5 ENST00000383168.9 NP_001641.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AQP4ENST00000383168.9 linkuse as main transcriptc.812A>G p.Gln271Arg missense_variant 5/51 NM_001650.7 ENSP00000372654 P1P55087-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152246
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152246
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000340

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 17, 2023The c.812A>G (p.Q271R) alteration is located in exon 5 (coding exon 5) of the AQP4 gene. This alteration results from a A to G substitution at nucleotide position 812, causing the glutamine (Q) at amino acid position 271 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.44
T;.;.
Eigen
Benign
-0.11
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.90
D;.;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
1.9
L;.;.
MutationTaster
Benign
0.99
D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.2
N;.;.
REVEL
Benign
0.16
Sift
Benign
0.11
T;.;.
Sift4G
Benign
0.49
T;T;T
Polyphen
0.019
B;.;.
Vest4
0.068
MVP
0.91
MPC
0.14
ClinPred
0.44
T
GERP RS
5.8
Varity_R
0.19
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886513761; hg19: chr18-24436335; COSMIC: COSV101270465; COSMIC: COSV101270465; API