rs202134424

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001282225.2(ADA2):c.139G>T(p.Gly47Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G47A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.43

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a turn (size 3) in uniprot entity ADA2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001282225.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-17209538-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 120301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 22-17209539-C-A is Pathogenic according to our data. Variant chr22-17209539-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 541731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2 linkuse as main transcript	c.139G>T	p.Gly47Trp	missense_variant	2/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8 linkuse as main transcript	c.139G>T	p.Gly47Trp	missense_variant	2/10	1	NM_001282225.2	P1	Q9NZK5-1

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251330

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Published functional studies demonstrate that cells with this variant have 0.3% of enzymatic activity compared with wild-type (Lee et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34004258, 29600946, 31686313, 31945408, 33021335, 24552285, 24552284) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ADA2: PM3:Very Strong, PM2, PM5 -
Pathogenic, criteria provided, single submitter	curation	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2023	The ADA2 c.139G>T; p.Gly47Trp variant (rs202134424) is reported in the literature in compound heterozygous and homozygous individuals with symptoms of deficiency of adenosine deaminase 2 (DADA2) (Goschl 2020, Lamprecht 2018, Lee 2020). This variant is reported in ClinVar (Variation ID: 541731) and is only observed on one allele in the Genome Aggregation Database (v2.1.1), which indicates that it is not a common polymorphism. Additionally, other variants at this codon (c.140G>C, p.G47A; c.139G>A, p.G47R; c.139G>C, p.G47R; c.140G>T, p.G47V) have been reported in individuals with DADA2 and are considered pathogenic or likely pathogenic (Caorsi 2017, Garg 2014, Gibson 2019, Gunthner 2018, Nanthapisal 2016, Navon Elkan 2014, Ozen 2019, Poswar Fde 2016, Schepp 2017, Skrabl-Baumgartner 2017, Van Eyck 2014, Zhou 2014). Computational analyses predict that the p.Gly47Trp variant is deleterious (REVEL: 0.875). Functional analyses of the variant protein show less than 2% enzymatic activity compared to wildtype protein (Lee 2020). Based on available information, the p.Gly47Trp variant is considered to be pathogenic. References: Caorsi et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017 Oct;76(10):1648-1656. PMID: 28522451. Garg et al. Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr. 2014 Jun;173(6):827-30. PMID: 24737293. Gibson et al. Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis. Arthritis Rheumatol. 2019 Oct;71(10):1747-1755. PMID: 31008556. Goschl L et al. Unreported Missense Mutation in the Dimerization Domain of ADA2 Leads to ADA2 Deficiency Associated with Severe Oral Ulcers and Neutropenia in a Female Somalian Patient-Addendum to the Genotype-Phenotype Puzzle. J Clin Immunol. 2020 Jan;40(1):223-226. PMID: 31686313. Gunthner et al. Identification of co-occurrence in a patient with Dent's disease and ADA2-deficiency by exome sequencing. Gene. 2018 Apr 5;649:23-26. PMID: 29391272. Lamprecht P et al. Diagnosis of deficiency of adenosine deaminase 2 with early onset polyarteritis nodosa in an adult patient with a novel compound heterozygous CECR1 mutation. Clin Exp Rheumatol. 2018 Mar-Apr;36 Suppl 111(2):177. Epub 2018 Mar 15. PMID: 29600946. Lee PY et al. Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020 Jun;145(6):1664-1672.e10. PMID: 31945408. Nanthapisal et al. Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases. Arthritis Rheumatol. 2016 Sep;68(9):2314-22. PMID: 27059682. Navon Elkan et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014 Mar 6;370(10):921-31. PMID: 24552285. Ozen et al. A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2. J Rheumatol. 2019 May 1. pii: jrheum.181384. PMID: 31043544. Poswar Fde et al. Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. J Neurol. 2016 Apr;263(4):818-20. PMID: 26914925. Schepp et al. Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood. Arthritis Rheumatol. 2017 Aug;69(8):1689-1700. PMID: 28493328. Skrabl-Baumgartner et al. Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatr Rheumatol Online J. 2017 Aug 22;15(1):67. PMID: 28830446. Van Eyck et al. Mutant ADA2 in vasculopathies. N Engl J Med. 2014 Jul 31;371(5):480. PMID: 25075848. Zhou et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911-20. PMID: 24552284. -

Vasculitis due to ADA2 deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 10, 2023	For these reasons, this variant has been classified as Pathogenic. 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). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADA2 protein function. ClinVar contains an entry for this variant (Variation ID: 541731). This missense change has been observed in individual(s) with clinical features consistent with deficiency of adenosine deaminase 2 (DADA2) (PMID: 29600946, 31686313; Invitae). This variant is present in population databases (rs202134424, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 47 of the ADA2 protein (p.Gly47Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Uncertain

0.99

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

0.69

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

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

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

MetaSVM

Uncertain

0.20

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.9

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

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.75

MutPred

0.86

Loss of disorder (P = 0.0256);Loss of disorder (P = 0.0256);Loss of disorder (P = 0.0256);Loss of disorder (P = 0.0256);.;.;Loss of disorder (P = 0.0256);Loss of disorder (P = 0.0256);

MVP

0.69

MPC

0.33

ClinPred

0.99

GERP RS

4.8

Varity_R

0.84

gMVP

0.85

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

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