22-17209539-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_StrongPM5PP3_StrongPP5_Very_Strong

The NM_001282225.2(ADA2):c.139G>A(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,980 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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G47W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 6.43

Publications

55 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: Pathogenic. The variant received 22 ACMG points.

PS1

Transcript NM_001282225.2 (ADA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-17209539-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 541731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 22-17209539-C-T is Pathogenic according to our data. Variant chr22-17209539-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 120304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2 link	c.139G>A	p.Gly47Arg	missense_variant	Exon 2 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.139G>A	p.Gly47Arg	missense_variant	Exon 2 of 10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251330

AF XY:

0.000140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000777

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112006

Other (OTH)

AF:

0.000132

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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

AF:

0.0000394

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.0000656

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

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:

0.0000941

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Pathogenic:11Other:1

Jan 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CECR1 (ADA2) c.139G>A (p.Gly47Arg) results in a non-conservative amino acid change located in the Adenosine/AMP deaminase N-terminal domain (IPR013659) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251330 control chromosomes (gnomAD). c.139G>A has been reported in the literature in multiple individuals affected with ADA2 Deficiency/Polyarteritis Nodosa, primarily with a childhood onset and has been found to segregate with disease in several families (e.g. Navon Elkan_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found that variant effect results in <10% of normal activity (Jee_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34004258, 24552285). ClinVar contains an entry for this variant (Variation ID: 120304). Based on the evidence outlined above, the variant was classified as pathogenic. -

Suma Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A missense variant c.139G>A, p.(Gly47Arg) is observed in exon 2 of ADA2 in homozygous state in the proband. This variant is observed in 108 individuals in the gnomAD database in heterozygous state. ACMG Classification: Pathogenic Criteria met: PS1_Strong: Same amino acid change as a known pathogenic variant. PS3_Supporting: Well-established functional studies show damaging effect on the gene or gene product. PM2_Supporting: Extremely low frequency in gnomAD population databases. PM3_Very strong: For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases. -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the ADA2 protein (p.Gly47Arg). This variant is present in population databases (rs202134424, gnomAD 0.07%). This missense change has been observed in individuals with ADA2 deficiency and polyarteritis nodosa (PMID: 24552284, 24552285, 25075844, 25278816, 26914925, 27059682, 28522451, 28830446). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 120304). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ADA2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24552284, 24552285, 28493328, 28522451, 29391272). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This ADA2 variant (rs202134424) has been reported to segregate with disease in multiple unrelated families with ADA2-deficiency. It is rare (> or = 0.1%) in large population datasets (gnomAD: 30/282718 total alleles; 0.01%; no homozygotes). Two submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant is located within the dimerization domain of ADA2 and is thought to affect the stability of homodimers or their individual subunits. Functional studies have shown that levels of ADA2 in multiple cell types were significantly lower in mutant proteins compared to non-mutant proteins, supporting the pathogenicity of this variant. Multiple alternate pathogenic missense variants have been reported within the same residue (p.Gly47Ala; p.Gly47Val). ADA2 c.139G>A is considered pathogenic. -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.139G>A(p.Gly47Arg) in ADA2 gene has been has been observed in compound heterozygous state in multiple individuals with ADA2 deficiency and polyarteritis nodosa (Skrabl-Baumgartner et. al., 2017; Caorsi et. al., 2017). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects ADA2 function (Navon et. al., 2014). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Günthner et. al., 2018). The observed variant has alllele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Gly47Arg in ADA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 47 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 23, 2022

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 19, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Pathogenic:1

Dec 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADA2: PS1, PM1, PM2, PM3, PM5, PP4:Moderate, PS3:Supporting -

Autoinflammatory syndrome

Pathogenic:1

Nov 26, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sneddon syndrome

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D;D;.;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

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

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.20

PhyloP100

6.4

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.7

D;D;D;.;D;.;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;.;D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;.;D;.;D;.

Polyphen

1.0

D;D;D;D;.;.;.;.

Vest4

0.93

MutPred

0.81

Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);.;.;Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);

MVP

0.78

MPC

0.33

ClinPred

0.92

GERP RS

4.8

PromoterAI

0.014

Neutral

(source)

Varity_R

0.96

gMVP

0.85

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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