15-58166742-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_020980.5(AQP9):ā€‹c.181A>Gā€‹(p.Asn61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,658 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 (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

AQP9
NM_020980.5 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AQP9NM_020980.5 linkc.181A>G p.Asn61Asp missense_variant Exon 2 of 6 ENST00000219919.9 NP_066190.2 O43315
AQP9NM_001320635.2 linkc.181A>G p.Asn61Asp missense_variant Exon 2 of 5 NP_001307564.1
AQP9NM_001320636.1 linkc.-15A>G 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
AQP9ENST00000219919.9 linkc.181A>G p.Asn61Asp missense_variant Exon 2 of 6 1 NM_020980.5 ENSP00000219919.4 O43315

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461658
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.181A>G (p.N61D) alteration is located in exon 2 (coding exon 2) of the AQP9 gene. This alteration results from a A to G substitution at nucleotide position 181, causing the asparagine (N) at amino acid position 61 to be replaced by an aspartic acid (D). 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
Uncertain
0.50
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.76
.;T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.6
M;M
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Uncertain
0.39
Sift
Benign
0.031
D;D
Sift4G
Uncertain
0.024
D;D
Polyphen
0.99
D;D
Vest4
0.59
MutPred
0.60
Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP
0.92
MPC
0.047
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.33
gMVP
0.84

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.

Other links and lift over

dbSNP: rs1180276406; hg19: chr15-58458941; API