22-17203656-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_001282225.2(ADA2):c.660C>A(p.Tyr220*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,564 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y220Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.0130

Publications

2 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 19 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 22-17203656-G-T is Pathogenic according to our data. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17203656-G-T is described in CliVar as Pathogenic. Clinvar id is 2889771.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.660C>A	p.Tyr220*	stop_gained	Exon 4 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.660C>A	p.Tyr220*	stop_gained	Exon 4 of 10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251458

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Pathogenic:1

Sep 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with DADA2 deficiency (PMID: 28974505). This variant is present in population databases (rs2231487, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr220*) in the ADA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA2 are known to be pathogenic (PMID: 24552284, 24552285). -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Pathogenic:1

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.58

PhyloP100

0.013

Vest4

0.85

GERP RS

-3.9

Mutation Taster

=17/183

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.69

Position offset: -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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over