9-33447426-C-A

Variant names:

• chr9-33447426-C-A
• rs591810
• NM_004925.5:c.105G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004925.5(AQP3):​c.105G>T​(p.Leu35Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000484 in 1,446,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L35L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AQP3 NM_004925.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0520
• Publications: 24 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004925.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP3	NM_004925.5	MANE Select	c.105G>T	p.Leu35Leu	synonymous	Exon 1 of 6	NP_004916.1	Q92482-1
	AQP3	NM_001318144.2		c.105G>T	p.Leu35Leu	synonymous	Exon 1 of 5	NP_001305073.1	A0A2R8Y2R4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP3	ENST00000297991.6	TSL:1 MANE Select	c.105G>T	p.Leu35Leu	synonymous	Exon 1 of 6	ENSP00000297991.4	Q92482-1
	AQP3	ENST00000969970.1		c.105G>T	p.Leu35Leu	synonymous	Exon 1 of 5	ENSP00000640029.1
	AQP3	ENST00000645858.1		c.105G>T	p.Leu35Leu	synonymous	Exon 1 of 5	ENSP00000493516.1	A0A2R8Y2R4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000275 AC: 6 AN: 218270 AF XY: 0.0000338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000484 AC: 7 AN: 1446294 Hom.: 0 Cov.: 40 AF XY: 0.00000696 AC XY: 5 AN XY: 717974

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.000118 AC: 5 AN: 42484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39038

South Asian (SAS) AF: 0.00 AC: 0 AN: 83778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51716

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104694

Other (OTH) AF: 0.00 AC: 0 AN: 59764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00287062), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 9557

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		0.052
PromoterAI		0.030	Neutral

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

Other links and lift over

dbSNP: rs591810; hg19: chr9-33447424;