rs149078840

Variant names:

• chr22-17207064-T-C
• rs149078840
• NM_001282225.2:c.542+7A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001282225.2(ADA2):​c.542+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,610,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ADA2 NM_001282225.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003258
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.995
• Publications: 0 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 22-17207064-T-C is Benign according to our data. Variant chr22-17207064-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (222/152344) while in subpopulation AFR AF = 0.00515 (214/41582). AF 95% confidence interval is 0.00458. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.542+7A>G		splice_region intron	N/A	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.542+7A>G		splice_region intron	N/A	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.416+7A>G		splice_region intron	N/A	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.542+7A>G		splice_region intron	N/A	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.542+7A>G		splice_region intron	N/A	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.542+7A>G		splice_region intron	N/A	ENSP00000555418.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000402 AC: 101 AN: 250954 AF XY: 0.000295

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000204 AC: 297 AN: 1457658 Hom.: 0 Cov.: 30 AF XY: 0.000190 AC XY: 138 AN XY: 725402

African (AFR) AF: 0.00485 AC: 162 AN: 33398

American (AMR) AF: 0.0000895 AC: 4 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1108300

Other (OTH) AF: 0.000282 AC: 17 AN: 60232

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74506

African (AFR) AF: 0.00515 AC: 214 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.00179

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ADA2-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.36
DANN	Benign	0.46
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs149078840; hg19: chr22-17687954;