9-33443441-C-A

Variant names:

• chr9-33443441-C-A
• NM_004925.5:c.253G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004925.5(AQP3):​c.253G>T​(p.Ala85Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AQP3 NM_004925.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

Genes affected

AQP3 (HGNC:636): (aquaporin 3 (Gill blood group)) This gene encodes the water channel protein aquaporin 3. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein, also known as aquaporin 0. Aquaporin 3 is localized at the basal lateral membranes of collecting duct cells in the kidney. In addition to its water channel function, aquaporin 3 has been found to facilitate the transport of nonionic small solutes such as urea and glycerol, but to a smaller degree. It has been suggested that water channels can be functionally heterogeneous and possess water and solute permeation mechanisms. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP3	NM_004925.5	c.253G>T	p.Ala85Ser	missense_variant	Exon 3 of 6	ENST00000297991.6	NP_004916.1
AQP3	NM_001318144.2	c.253G>T	p.Ala85Ser	missense_variant	Exon 3 of 5		NP_001305073.1
AQP3	XM_047423348.1	c.253G>T	p.Ala85Ser	missense_variant	Exon 3 of 4		XP_047279304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP3	ENST00000297991.6	c.253G>T	p.Ala85Ser	missense_variant	Exon 3 of 6	1	NM_004925.5	ENSP00000297991.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>T (p.A85S) alteration is located in exon 3 (coding exon 3) of the AQP3 gene. This alteration results from a G to T substitution at nucleotide position 253, causing the alanine (A) at amino acid position 85 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.018	D;.
Polyphen		0.96	D;.
Vest4		0.75
MutPred		0.92		Gain of glycosylation at A85 (P = 0.0525);Gain of glycosylation at A85 (P = 0.0525);
MVP		0.63
MPC		1.2
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.67
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-33443439;