rs771895202

Variant names:

• chr9-33386402-A-G
• rs771895202
• NM_001170.3:c.406+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PVS1_Strong PM2 BP6_Moderate

The NM_001170.3(AQP7):​c.406+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AQP7 NM_001170.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.04
• Publications: 4 publications found

Genes affected

AQP7 (HGNC:640): (aquaporin 7) This gene encodes a member of the aquaporin family of water-selective membrane channels. The encoded protein localizes to the plasma membrane and allows movement of water, glycerol and urea across cell membranes. This gene is highly expressed in the adipose tissue where the encoded protein facilitates efflux of glycerol. In the proximal straight tubules of kidney, the encoded protein is localized to the apical membrane and prevents excretion of glycerol into urine. The encoded protein is present in spermatids, as well as in the testicular and epididymal spermatozoa suggesting an important role in late spermatogenesis. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene is located adjacent to a related aquaporin gene on chromosome 9. Multiple pseudogenes of this gene have been identified. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1341108 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-33386402-A-G is Benign according to our data. Variant chr9-33386402-A-G is described in ClinVar as Benign. ClinVar VariationId is 402388.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170.3. 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
	AQP7	NM_001170.3	MANE Select	c.406+2T>C		splice_donor intron	N/A	NP_001161.1	O14520-1
	AQP7	NM_001376191.1		c.406+2T>C		splice_donor intron	N/A	NP_001363120.1	O14520-1
	AQP7	NM_001376192.1		c.406+2T>C		splice_donor intron	N/A	NP_001363121.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AQP7	ENST00000297988.6	TSL:1 MANE Select	c.406+2T>C		splice_donor intron	N/A	ENSP00000297988.1	O14520-1
	AQP7	ENST00000377425.8	TSL:1	c.235+2T>C		splice_donor intron	N/A	ENSP00000396111.2	Q6P5T0
	AQP7	ENST00000537089.5	TSL:1	n.*126+2T>C		splice_donor intron	N/A	ENSP00000441619.2	A0A096LNU3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0117 AC: 1853 AN: 158716 AF XY: 0.00903

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.00510

Gnomad EAS exome AF: 0.00497

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0104

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.224 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.0
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs771895202;

hg19: chr9-33386400;

COSMIC: COSV53004383;

COSMIC: COSV53004383;