chr22-17188375-C-T

Variant names:

• chr22-17188375-C-T
• rs74317375
• NM_001282225.2:c.1045G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001282225.2(ADA2):​c.1045G>A​(p.Val349Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,614,100 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: -1.29
• Publications: 9 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)
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005244136).
• BP6: Variant 22-17188375-C-T is Benign according to our data. Variant chr22-17188375-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 430693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (339/152338) while in subpopulation NFE AF = 0.00388 (264/68030). AF 95% confidence interval is 0.0035. There are 1 homozygotes in GnomAd4. There are 152 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	NM_001282225.2	MANE Select	c.1045G>A	p.Val349Ile	missense	Exon 7 of 10	NP_001269154.1
	ADA2	NM_001282226.2		c.1045G>A	p.Val349Ile	missense	Exon 7 of 10	NP_001269155.1
	ADA2	NM_001282227.2		c.919G>A	p.Val307Ile	missense	Exon 7 of 10	NP_001269156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	ENST00000399837.8	TSL:1 MANE Select	c.1045G>A	p.Val349Ile	missense	Exon 7 of 10	ENSP00000382731.2
	ADA2	ENST00000262607.3	TSL:1	c.1045G>A	p.Val349Ile	missense	Exon 6 of 9	ENSP00000262607.2
	ADA2	ENST00000885359.1		c.1162G>A	p.Val388Ile	missense	Exon 8 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152220 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00211 AC: 530 AN: 251316 AF XY: 0.00213

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.00348

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00332 AC: 4858 AN: 1461762 Hom.: 13 Cov.: 31 AF XY: 0.00325 AC XY: 2360 AN XY: 727188

African (AFR) AF: 0.000597 AC: 20 AN: 33476

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86252

European-Finnish (FIN) AF: 0.000824 AC: 44 AN: 53394

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00398 AC: 4429 AN: 1111928

Other (OTH) AF: 0.00369 AC: 223 AN: 60390

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152338 Hom.: 1 Cov.: 34 AF XY: 0.00204 AC XY: 152 AN XY: 74492

African (AFR) AF: 0.000914 AC: 38 AN: 41592

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00316 Hom.: 3

Bravo AF: 0.00243

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00217 AC: 263

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Vasculitis due to ADA2 deficiency (2)
-	-	1	ADA2-related disorder (1)
-	-	1	Autoinflammatory syndrome (1)
1	-	-	Behcet disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.16
DANN	Benign	0.83
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0052	T
MetaSVM	Uncertain	-0.27	T
PhyloP100		-1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.26
Sift	Benign	0.16	T
Sift4G	Benign	0.39	T
Polyphen		0.066	B
Vest4		0.071
MVP		0.43
MPC		0.039
ClinPred		0.0022	T
GERP RS		-8.2
Varity_R		0.063
gMVP		0.14
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs74317375; hg19: chr22-17669265;