Genetic Variant AQP12A:p.Thr83Ala (chr2-240692197-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198998.3(AQP12A):c.247A>G(p.Thr83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 1,581,312 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T83T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000070 ( 2 hom. )

Consequence

AQP12A
NM_198998.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.79

Variant links:

Genes affected

AQP12A (HGNC:19941): (aquaporin 12A) Predicted to enable channel activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AQP12A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053901553).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AQP12A	NM_198998.3 link	c.247A>G	p.Thr83Ala	missense_variant	Exon 2 of 4	ENST00000337801.9	NP_945349.1	Q8IXF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AQP12A	ENST00000337801.9 link	c.247A>G	p.Thr83Ala	missense_variant	Exon 2 of 4	1	NM_198998.3	ENSP00000337144.4		Q8IXF9

Frequencies

GnomAD3 genomes

AF:

0.00000689

AC:

AN:

145130

Hom.:

Cov.:

show subpopulations

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

240954

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131224

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:

0.0000673

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000696

AC:

AN:

1436182

Hom.:

Cov.:

AF XY:

0.00000839

AC XY:

AN XY:

714862

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:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000727

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000689

AC:

AN:

145130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70656

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000149

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000568

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247A>G (p.T83A) alteration is located in exon 2 (coding exon 2) of the AQP12A gene. This alteration results from a A to G substitution at nucleotide position 247, causing the threonine (T) at amino acid position 83 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.040

DANN

Benign

0.64

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.32

N;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.011

Sift

Benign

0.39

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.0030

B;.

Vest4

0.058

MutPred

0.47

Loss of glycosylation at T83 (P = 0.0216);.;

MVP

0.055

MPC

0.35

ClinPred

0.094

GERP RS

-2.9

Varity_R

0.038

gMVP

0.33

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