15-58166710-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020980.5(AQP9):c.149G>T(p.Ser50Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

AQP9
NM_020980.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.00

Variant links:

Genes affected

AQP9 (HGNC:643): (aquaporin 9) The aquaporins are a family of water-selective membrane channels. This gene encodes a member of a subset of aquaporins called the aquaglyceroporins. This protein allows passage of a broad range of noncharged solutes and also stimulates urea transport and osmotic water permeability. This protein may also facilitate the uptake of glycerol in hepatic tissue . The encoded protein may also play a role in specialized leukocyte functions such as immunological response and bactericidal activity. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

AQP9 links:

ALDH1A2 (HGNC:15472): (aldehyde dehydrogenase 1 family member A2) This protein belongs to the aldehyde dehydrogenase family of proteins. The product of this gene is an enzyme that catalyzes the synthesis of retinoic acid (RA) from retinaldehyde. Retinoic acid, the active derivative of vitamin A (retinol), is a hormonal signaling molecule that functions in developing and adult tissues. The studies of a similar mouse gene suggest that this enzyme and the cytochrome CYP26A1, concurrently establish local embryonic retinoic acid levels which facilitate posterior organ development and prevent spina bifida. Four transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2011]

ALDH1A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP9	NM_020980.5 link	c.149G>T	p.Ser50Ile	missense_variant	Exon 2 of 6	ENST00000219919.9	NP_066190.2	O43315
AQP9	NM_001320635.2 link	c.149G>T	p.Ser50Ile	missense_variant	Exon 2 of 5		NP_001307564.1
AQP9	NM_001320636.1 link	c.-47G>T		5_prime_UTR_variant	Exon 2 of 6		NP_001307565.1	H0YK62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP9	ENST00000219919.9 link	c.149G>T	p.Ser50Ile	missense_variant	Exon 2 of 6	1	NM_020980.5	ENSP00000219919.4		O43315

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

250266

Hom.:

AF XY:

0.0000887

AC XY:

AN XY:

135264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

307

AN:

1460938

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.000269

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000179

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149G>T (p.S50I) alteration is located in exon 2 (coding exon 2) of the AQP9 gene. This alteration results from a G to T substitution at nucleotide position 149, causing the serine (S) at amino acid position 50 to be replaced by an isoleucine (I). 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

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.96

MPC

0.067

ClinPred

0.83

GERP RS

4.8

Varity_R

0.81

gMVP

0.80

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over