12-49962105-G-A

Position:

chr12-49962105-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001651.4(AQP5):c.88G>A(p.Gly30Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

AQP5
NM_001651.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.37

Variant links:

Genes affected

AQP5 (HGNC:638): (aquaporin 5) Aquaporin 5 (AQP5) is a water channel protein. Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). Aquaporin 5 plays a role in the generation of saliva, tears and pulmonary secretions. AQP0, AQP2, AQP5, and AQP6 are closely related and all map to 12q13. [provided by RefSeq, Jul 2008]

AQP5 links:

AQP5-AS1 (HGNC:55474): (AQP5 and AQP2 antisense RNA 2)

AQP5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP5	NM_001651.4 link	c.88G>A	p.Gly30Ser	missense_variant	Exon 1 of 4	ENST00000293599.7	NP_001642.1	P55064

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AQP5	ENST00000293599.7 link	c.88G>A	p.Gly30Ser	missense_variant	Exon 1 of 4	1	NM_001651.4	ENSP00000293599.5	P55064
AQP5-AS1	ENST00000550214.1 link	n.258+562C>T		intron_variant	Intron 1 of 1	2
AQP5-AS1	ENST00000550530.1 link	n.117+562C>T		intron_variant	Intron 1 of 2	3
AQP5-AS1	ENST00000552379.1 link	n.256+562C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250372

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726948

show subpopulations

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The AQP5 p.Gly30Ser variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs139623970) and LOVD 3.0 (not classified). The variant was identified in control databases in 2 of 281716 chromosomes at a frequency of 0.000007099 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 2 of 128342 chromosomes (freq: 0.000016), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Gly30 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.78

Sift

Benign

0.17

Sift4G

Benign

0.15

Polyphen

0.85

Vest4

0.81

MutPred

0.85

Loss of sheet (P = 0.1158);

MVP

0.97

MPC

0.88

ClinPred

0.98

GERP RS

3.8

Varity_R

0.74

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over