Genetic Variant AQP5:p.Val119Ile (chr12-49962372-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001651.4(AQP5):c.355G>A(p.Val119Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000836 in 1,435,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AQP5
NM_001651.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0800

Publications

1 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16956523).

BP6

Variant 12-49962372-G-A is Benign according to our data. Variant chr12-49962372-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2608648.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001651.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AQP5	NM_001651.4	MANE Select	c.355G>A	p.Val119Ile	missense	Exon 1 of 4	NP_001642.1	P55064
AQP5-AS1	NR_110589.1		n.258+295C>T		intron	N/A
AQP5-AS1	NR_110590.1		n.256+295C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AQP5	ENST00000293599.7	TSL:1 MANE Select	c.355G>A	p.Val119Ile	missense	Exon 1 of 4	ENSP00000293599.5	P55064
AQP5	ENST00000857226.1		c.355G>A	p.Val119Ile	missense	Exon 1 of 3	ENSP00000527285.1
AQP5-AS1	ENST00000550214.2	TSL:2	n.286+295C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

132730

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000306

AC:

AN:

196024

AF XY:

0.0000276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000689

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000548

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000836

AC:

AN:

1435050

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31904

American (AMR)

AF:

0.00

AC:

AN:

43406

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.0000789

AC:

AN:

38040

South Asian (SAS)

AF:

0.00

AC:

AN:

84458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00000815

AC:

AN:

1104920

Other (OTH)

AF:

0.00

AC:

AN:

59096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

132830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64040

African (AFR)

AF:

0.00

AC:

AN:

35852

American (AMR)

AF:

0.00

AC:

AN:

12840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3284

East Asian (EAS)

AF:

0.00

AC:

AN:

4290

South Asian (SAS)

AF:

0.00

AC:

AN:

3702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61514

Other (OTH)

AF:

0.00

AC:

AN:

1748

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000417

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Benign

-0.35

CADD

Benign

6.2

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.39

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.64

M_CAP

Benign

0.058

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.52

PhyloP100

0.080

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.090

REVEL

Benign

0.20

Sift

Benign

0.29

Sift4G

Benign

0.35

Polyphen

0.010

Vest4

0.094

MutPred

0.56

Loss of methylation at R114 (P = 0.1542)

MVP

0.62

MPC

0.30

ClinPred

0.032

GERP RS

2.8

Varity_R

0.049

gMVP

0.40

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over