15-58184082-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020980.5(AQP9):c.835A>G(p.Thr279Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,613,952 control chromosomes in the GnomAD database, including 715,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.90 (61949 hom., cov: 30)
  • Exomes 𝑓: 0.94 (653580 hom.)
• Consequence: AQP9 NM_020980.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.974237E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AQP9	NM_020980.5	c.835A>G	p.Thr279Ala	missense_variant	6/6	ENST00000219919.9
AQP9	NM_001320636.1	c.640A>G	p.Thr214Ala	missense_variant	6/6
AQP9	NM_001320635.2	c.*35A>G		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AQP9	ENST00000219919.9	c.835A>G	p.Thr279Ala	missense_variant	6/6	1	NM_020980.5	P1

Frequencies

GnomAD3 genomes AF: 0.899 AC: 136647 AN: 152026 Hom.: 61913 Cov.: 30

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.973

Gnomad AMR AF: 0.926

Gnomad ASJ AF: 0.963

Gnomad EAS AF: 0.828

Gnomad SAS AF: 0.870

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.960

Gnomad OTH AF: 0.915

GnomAD3 exomes AF: 0.919 AC: 231148 AN: 251388 Hom.: 106634 AF XY: 0.921 AC XY: 125080 AN XY: 135852

Gnomad AFR exome AF: 0.778

Gnomad AMR exome AF: 0.919

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.841

Gnomad SAS exome AF: 0.869

Gnomad FIN exome AF: 0.943

Gnomad NFE exome AF: 0.956

Gnomad OTH exome AF: 0.941

GnomAD4 exome AF: 0.945 AC: 1381081 AN: 1461808 Hom.: 653580 Cov.: 53 AF XY: 0.943 AC XY: 685864 AN XY: 727202

Gnomad4 AFR exome AF: 0.779

Gnomad4 AMR exome AF: 0.919

Gnomad4 ASJ exome AF: 0.966

Gnomad4 EAS exome AF: 0.853

Gnomad4 SAS exome AF: 0.873

Gnomad4 FIN exome AF: 0.942

Gnomad4 NFE exome AF: 0.960

Gnomad4 OTH exome AF: 0.932

GnomAD4 genome AF: 0.899 AC: 136740 AN: 152144 Hom.: 61949 Cov.: 30 AF XY: 0.897 AC XY: 66750 AN XY: 74388

Gnomad4 AFR AF: 0.781

Gnomad4 AMR AF: 0.926

Gnomad4 ASJ AF: 0.963

Gnomad4 EAS AF: 0.828

Gnomad4 SAS AF: 0.870

Gnomad4 FIN AF: 0.942

Gnomad4 NFE AF: 0.960

Gnomad4 OTH AF: 0.916

Alfa AF: 0.944 Hom.: 141073

Bravo AF: 0.894

TwinsUK AF: 0.960 AC: 3558

ALSPAC AF: 0.957 AC: 3687

ESP6500AA AF: 0.790 AC: 3462

ESP6500EA AF: 0.957 AC: 8217

ExAC AF: 0.915 AC: 111059

Asia WGS AF: 0.836 AC: 2907 AN: 3478

EpiCase AF: 0.959

EpiControl AF: 0.956

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.47
Dann	Benign	0.64
DEOGEN2	Benign	0.020	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.12	T;.;T
MetaRNN	Benign	8.0e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.080	N;N;N
Sift	Benign	0.86	T;T;T
Sift4G	Benign	0.87	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.014
MPC		0.010
ClinPred		0.010	T
GERP RS		-3.7
Varity_R		0.027
gMVP		0.58

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

Other links and lift over

dbSNP: rs1867380; hg19: chr15-58476281; COSMIC: COSV54970435;