9-33442300-C-T

Variant names:

• chr9-33442300-C-T
• rs1347380973
• NM_004925.5:c.710+1G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004925.5(AQP3):​c.710+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000089 in 1,460,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AQP3 NM_004925.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 6.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP3	NM_004925.5	c.710+1G>A		splice_donor_variant, intron_variant	Intron 5 of 5	ENST00000297991.6	NP_004916.1
AQP3	NM_001318144.2	c.493-89G>A		intron_variant	Intron 4 of 4		NP_001305073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP3	ENST00000297991.6	c.710+1G>A		splice_donor_variant, intron_variant	Intron 5 of 5	1	NM_004925.5	ENSP00000297991.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460340 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726434

Gnomad4 AFR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000668 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

GIL BLOOD GROUP Other:1

Nov 29, 2002

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: -3
DS_DL_spliceai		0.93		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1347380973; hg19: chr9-33442298; COSMIC: COSV99955714; COSMIC: COSV99955714;