rs200930463

Positions:

• chr22-17209538-C-A
• chr22-17209538-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001282225.2(ADA2):​c.140G>T​(p.Gly47Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,586 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G47A) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a turn (size 3) in uniprot entity ADA2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001282225.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-17209538-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 120301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 22-17209538-C-A is Pathogenic according to our data. Variant chr22-17209538-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-17209538-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2	c.140G>T	p.Gly47Val	missense_variant	2/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8	c.140G>T	p.Gly47Val	missense_variant	2/10	1	NM_001282225.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251366 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461454 Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22 AN XY: 727040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Observed with a second variant in the ADA2 gene, including multiple instances of a different pathogenic variant confirmed on the opposite allele (in trans), in unrelated patients with features consistent with ADA2 deficiency in published literature (Navon Elkan et al., 2014; Hashem et al., 2017; zen et al., 2020; Hashem et al., 2021; Yap et al., 2021); Published functional studies demonstrate a damaging effect: decreased expression of mutant protein (Navon Elkan et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34004258, 32531373, 31043544, 28522451, 28974505, 34324127, 24552285, 34657246) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 22, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Vasculitis due to ADA2 deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120306). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120301,VCV000120304,VCV001076271, PMID:24552284,29600946,24737293). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.909>=0.6, 3CNET: 0.896>=0.75). A missense variant is a common mechanism associated with Vasculitis, autoinflammation, immunodeficiency, and hematologic defects syndrome. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000515). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with vasculitis due to ADA2 deficiency (MONDO:0014306). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported (PMID: 24552285). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (30 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated A_deaminase_N domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These alternative changes, p.(Gly47Ala), p.(Gly47Trp) and p.(Gly47Arg), have been reported multiple times as likely pathogenic and pathogenic (ClinVar, PMID: 34324127). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and observed in both homozygous and compound heterozygous individuals with primary immunodeficiency or ADA2 deficiency (ClinVar, PMID: 34324127, PMID: 32531373). (SP) 1205 - This variant has been shown to be maternally inherited (by Sanger analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 02, 2023	This missense change has been observed in individuals with clinical features of ADA2-related conditions (PMID: 24552285, 28974505, 31043544; Invitae). This variant is present in population databases (rs200930463, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the ADA2 protein (p.Gly47Val). ClinVar contains an entry for this variant (Variation ID: 120306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADA2 protein function. Experimental studies have shown that this missense change affects ADA2 function (PMID: 24552285). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24552285, 26914925, 27059682, 28830446). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D;D;.;.;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.095	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.6	D;D;D;.;D;.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D;D;.;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;.;D;.;D;.
Polyphen		1.0	D;D;D;D;.;.;.;.
Vest4		0.88
MutPred		0.92		Loss of disorder (P = 0.0734);Loss of disorder (P = 0.0734);Loss of disorder (P = 0.0734);Loss of disorder (P = 0.0734);.;.;Loss of disorder (P = 0.0734);Loss of disorder (P = 0.0734);
MVP		0.82
MPC		0.34
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs200930463; hg19: chr22-17690428;