dbSNP rs1555661648: AQP4:p.Ser111Ile (chr18-26862297-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001650.7(AQP4):c.332G>T(p.Ser111Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S111T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AQP4
NM_001650.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.56

Publications

0 publications found

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 links:

AQP4-AS1 (HGNC:26399): (AQP4 antisense RNA 1)

AQP4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-26862297-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 446492.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP4	NM_001650.7	MANE Select	c.332G>T	p.Ser111Ile	missense	Exon 2 of 5	NP_001641.1
AQP4	NM_001317384.3		c.332G>T	p.Ser111Ile	missense	Exon 2 of 5	NP_001304313.1
AQP4	NM_001364287.1		c.266G>T	p.Ser89Ile	missense	Exon 2 of 5	NP_001351216.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AQP4	ENST00000383168.9	TSL:1 MANE Select	c.332G>T	p.Ser111Ile	missense	Exon 2 of 5	ENSP00000372654.4
AQP4	ENST00000581374.5	TSL:1	c.266G>T	p.Ser89Ile	missense	Exon 1 of 4	ENSP00000462597.1
AQP4	ENST00000672981.2		c.332G>T	p.Ser111Ile	missense	Exon 2 of 5	ENSP00000500598.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

7.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.83

Gain of methylation at K109 (P = 0.0419)

MVP

1.0

MPC

0.62

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.86

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over