Genetic Variant NM_001282225.2:c.1359T>C (chr22-17181903-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001282225.2(ADA2):c.1359T>C(p.Tyr453Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,613,476 control chromosomes in the GnomAD database, including 80,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6385 hom., cov: 32)

Exomes 𝑓: 0.31 ( 73665 hom. )

Consequence

ADA2
NM_001282225.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.458

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 22-17181903-A-G is Benign according to our data. Variant chr22-17181903-A-G is described in ClinVar as Benign. ClinVar VariationId is 402527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.458 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADA2	NM_001282225.2	MANE Select	c.1359T>C	p.Tyr453Tyr	synonymous	Exon 9 of 10	NP_001269154.1
ADA2	NM_001282226.2		c.1359T>C	p.Tyr453Tyr	synonymous	Exon 9 of 10	NP_001269155.1
ADA2	NM_001282227.2		c.1233T>C	p.Tyr411Tyr	synonymous	Exon 9 of 10	NP_001269156.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADA2	ENST00000399837.8	TSL:1 MANE Select	c.1359T>C	p.Tyr453Tyr	synonymous	Exon 9 of 10	ENSP00000382731.2
ADA2	ENST00000262607.3	TSL:1	c.1359T>C	p.Tyr453Tyr	synonymous	Exon 8 of 9	ENSP00000262607.2
ADA2	ENST00000885359.1		c.1476T>C	p.Tyr492Tyr	synonymous	Exon 10 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42457

AN:

151988

Hom.:

6387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.215

Gnomad ASJ

AF:

0.275

Gnomad EAS

AF:

0.0513

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.301

GnomAD2 exomes

AF:

0.256

AC:

64305

AN:

251404

AF XY:

0.258

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.283

Gnomad EAS exome

AF:

0.0475

Gnomad FIN exome

AF:

0.324

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.309

AC:

452265

AN:

1461370

Hom.:

73665

Cov.:

AF XY:

0.307

AC XY:

222977

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.231

AC:

7748

AN:

33470

American (AMR)

AF:

0.159

AC:

7092

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

7368

AN:

26122

East Asian (EAS)

AF:

0.0517

AC:

2051

AN:

39700

South Asian (SAS)

AF:

0.173

AC:

14914

AN:

86252

European-Finnish (FIN)

AF:

0.319

AC:

17053

AN:

53416

Middle Eastern (MID)

AF:

0.321

AC:

1844

AN:

5748

European-Non Finnish (NFE)

AF:

0.339

AC:

376491

AN:

1111558

Other (OTH)

AF:

0.293

AC:

17704

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

16245

32491

48736

64982

81227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11896

23792

35688

47584

59480

<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:

0.279

AC:

42470

AN:

152106

Hom.:

6385

Cov.:

AF XY:

0.273

AC XY:

20329

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.240

AC:

9949

AN:

41492

American (AMR)

AF:

0.215

AC:

3278

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

955

AN:

3470

East Asian (EAS)

AF:

0.0514

AC:

266

AN:

5178

South Asian (SAS)

AF:

0.164

AC:

792

AN:

4826

European-Finnish (FIN)

AF:

0.334

AC:

3532

AN:

10582

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22779

AN:

67956

Other (OTH)

AF:

0.297

AC:

628

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1514

3028

4543

6057

7571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.312

Hom.:

5121

Bravo

AF:

0.268

Asia WGS

AF:

0.114

AC:

396

AN:

3478

EpiCase

AF:

0.333

EpiControl

AF:

0.329

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.27

(source)

DANN

Benign

0.22

PhyloP100

0.46

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over