rs146597836

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001282225.2(ADA2):c.927G>A(p.Met309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M309T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:8

Conservation

PhyloP100: 1.07

Publications

9 publications found

Variant links:

Genes affected

ADA2 (HGNC:1839): (adenosine deaminase 2) This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ADA2 Gene-Disease associations (from GenCC):

deficiency of adenosine deaminase 2
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
vasculitis due to ADA2 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
polyarteritis nodosa
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
Sneddon syndrome
Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
Diamond-Blackfan anemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004589975).

BP6

Variant 22-17189987-C-T is Benign according to our data. Variant chr22-17189987-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 375247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00154 (2255/1461760) while in subpopulation MID AF = 0.012 (69/5766). AF 95% confidence interval is 0.0097. There are 4 homozygotes in GnomAdExome4. There are 1196 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2 link	c.927G>A	p.Met309Ile	missense_variant	Exon 6 of 10	ENST00000399837.8	NP_001269154.1	Q9NZK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8 link	c.927G>A	p.Met309Ile	missense_variant	Exon 6 of 10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00175

AC:

441

AN:

251468

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00154

AC:

2255

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1196

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.00161

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00215

AC:

185

AN:

86244

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00148

AC:

1648

AN:

1111918

Other (OTH)

AF:

0.00224

AC:

135

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

105

209

314

418

523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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

AF:

0.00159

AC:

242

AN:

152322

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41572

American (AMR)

AF:

0.00131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00188

AC:

128

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00177

Hom.:

Bravo

AF:

0.00173

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00198

AC:

240

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADA2: BS2 -

Jul 19, 2017

Blueprint Genetics

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Met309Ile variant in ADA2 is classified as benign because of its high frequency of 0.61% in Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146597836). This variant is present in ClinVar (variant ID 361951). Computational prediction tools and conservation analysis suggest that the p.Met309Ile variant may not impact the protein. ACMG/AMP criteria applied: BA1, BP4. -

Feb 16, 2022

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Behcet disease

Pathogenic:1

Jan 13, 2017

Department of Immunology, Hospital Universitario Virgen del Rocio

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Vasculitis due to ADA2 deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Mar 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ADA2-related disorder

Benign:1

Mar 05, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

9.5

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.024

T;T;T;.;T;T;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.57

T;.;.;T;.;T;.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.0046

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.55

PhyloP100

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

.;N;N;N;N;.;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.43

.;T;T;T;T;.;T;.

Sift4G

Benign

0.59

T;T;T;T;T;.;T;.

Polyphen

0.0020, 0.0

.;B;B;B;B;B;.;.

Vest4

0.29

MutPred

0.71

.;Loss of MoRF binding (P = 0.1393);Loss of MoRF binding (P = 0.1393);.;Loss of MoRF binding (P = 0.1393);Loss of MoRF binding (P = 0.1393);.;.;

MVP

0.71

MPC

0.048

ClinPred

0.0025

GERP RS

2.9

Varity_R

0.26

gMVP

0.53

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over