NM_001282225.2:c.139G>A

Variant names:

• chr22-17209539-C-T
• rs202134424
• NM_001282225.2:c.139G>A

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1_Very_Strong PS3 PM5 PP3_Strong PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000941825: Experimental studies have shown that this missense change affects ADA2 function (PMID:24552285).; SCV000992340: 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.; SCV002073342: Experimental studies have shown that this missense change affects ADA2 function (Navon et. al., 2014).; SCV004803992: "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)."; SCV006099837: "Well-established functional studies show damaging effect on the gene or gene product."". 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.43
• Publications: 56 publications found

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)
• Sneddon syndrome

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• polyarteritis nodosa

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_001282225.2 (ADA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000941825: Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285).; SCV000992340: 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.; SCV002073342: Experimental studies have shown that this missense change affects ADA2 function (Navon et. al., 2014).; SCV004803992: "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)."; SCV006099837: "Well-established functional studies show damaging effect on the gene or gene product."
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282225.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	NM_001282225.2	MANE Select	c.139G>A	p.Gly47Arg	missense	Exon 2 of 10	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.139G>A	p.Gly47Arg	missense	Exon 2 of 10	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.13G>A	p.Gly5Arg	missense	Exon 2 of 10	NP_001269156.1	B4E3Q4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	ENST00000399837.8	TSL:1 MANE Select	c.139G>A	p.Gly47Arg	missense	Exon 2 of 10	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.139G>A	p.Gly47Arg	missense	Exon 1 of 9	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.139G>A	p.Gly47Arg	missense	Exon 2 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152104 Hom.: 0 Cov.: 31

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: 27 AN: 251330 AF XY: 0.000140

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.: 0 Cov.: 34 AF XY: 0.000103 AC XY: 75 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112006

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000941 Hom.: 1

Bravo AF: 0.0000453

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Vasculitis due to ADA2 deficiency (11)
1	-	-	Autoinflammatory syndrome (1)
1	-	-	not provided (1)
1	-	-	Sneddon syndrome (1)
1	-	-	Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.20	D
PhyloP100		6.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.81		Gain of solvent accessibility (P = 0.0055)
MVP		0.78
MPC		0.33
ClinPred		0.92	D
GERP RS		4.8
PromoterAI		0.014	Neutral
Varity_R		0.96
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs202134424; hg19: chr22-17690429; COSMIC: COSV105005534; COSMIC: COSV105005534;