22-17209539-C-G

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>C(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,982 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely 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 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

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, 0.989

PP5

Variant 22-17209539-C-G is Pathogenic according to our data. Variant chr22-17209539-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1076271.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>C	p.Gly47Arg	missense_variant	Exon 2 of 10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8 link	c.139G>C	p.Gly47Arg	missense_variant	Exon 2 of 10	1	NM_001282225.2	ENSP00000382731.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251330

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000894

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:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

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:

0.00

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:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Pathogenic:3

Oct 26, 2024

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 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 24552285, 24737293, 25075844, 27059682, 28522451, 28830446, 31008556, 31291964). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1076271). 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%. For these reasons, this variant has been classified as Pathogenic. -

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

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense variant c.139G>C(p.Gly47Arg) in ADA2 gene has been reported previously in homozygous state in multiple individuals with vasculitis (Clarke K, et al., 2019, Gibson KM, et al., 2019). The same amino acid change (c.139G>A, p.Gly47Arg) and other variant(s) that disrupt this residue have been determined to be pathogenic (Günthner R, et al., 2018). The c.139G>C(p.Gly47Arg) variant is reported with 0.002% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen-probably damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. 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. The reference amino acid p.Gly47Arg in ADA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Jun 19, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADA2: PM3:Strong, PS1, PM1, PM2, PM5 -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Pathogenic:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Pathogenic:1

Oct 06, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ADA2-related disorder

Pathogenic:1

Apr 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ADA2 c.139G>C variant is predicted to result in the amino acid substitution p.Gly47Arg. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with ADA2-related disease (see for example - Nanthapisal et al. 2016. PubMed ID: 27059682; Skrabl-Baumgartner et al. 2017. PubMed ID: 28830446). Functional studies found this variant results in <20% of wild type activity (Jee et al. 2021. PubMed ID: 34004258). Additionally, an alternate nucleotide substitution (c.139G>A) resulting in the same missense variant and alternate missense variants affecting this residue (p.Gly47Trp, p.Gly47Ala, p.Gly47Val) have been reported as pathogenic (Karacan et al. 2019. PubMed ID: 30783801; Jee et al. 2021. PubMed ID: 34004258). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-17690429-C-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.19

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

0.76

MetaRNN

Pathogenic

0.99

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

0.96

GERP RS

4.8

PromoterAI

0.098

Neutral

(source)

Varity_R

0.96

gMVP

0.85

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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