rs1555887378

chr22-17209492-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001282225.2(ADA2):c.186G>T(p.Arg62Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0740

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a region_of_interest Dimerization (size 70) in uniprot entity ADA2_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_001282225.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3070716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2	c.186G>T	p.Arg62Ser	missense_variant	2/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8	c.186G>T	p.Arg62Ser	missense_variant	2/10	1	NM_001282225.2	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vasculitis due to ADA2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 18, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ADA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 62 of the ADA2 protein (p.Arg62Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	2.0
Dann	Benign	0.79
DEOGEN2	Benign	0.31	T;T;T;T;.;.;.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;N;.;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.40	T;T;T;.;T;.;T;T
Sift4G	Benign	0.47	T;T;T;.;T;.;D;.
Polyphen		0.14	B;B;B;B;.;.;.;.
Vest4		0.16
MutPred		0.57		Gain of phosphorylation at R62 (P = 0.0996);Gain of phosphorylation at R62 (P = 0.0996);Gain of phosphorylation at R62 (P = 0.0996);Gain of phosphorylation at R62 (P = 0.0996);.;.;Gain of phosphorylation at R62 (P = 0.0996);Gain of phosphorylation at R62 (P = 0.0996);
MVP		0.17
MPC		0.052
ClinPred		0.065	T
GERP RS		-2.4
Varity_R		0.68
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1555887378; hg19: chr22-17690382;