22-17209519-G-T

Variant names:

• chr22-17209519-G-T
• rs362129
• NM_001282225.2:c.159C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001282225.2(ADA2):​c.159C>A​(p.Asn53Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N53N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 23 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001282225.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17925295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.159C>A	p.Asn53Lys	missense_variant	Exon 2 of 10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.159C>A	p.Asn53Lys	missense_variant	Exon 2 of 10	1	NM_001282225.2	ENSP00000382731.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 79789

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.39
DANN	Benign	0.78
DEOGEN2	Uncertain	0.52	D;D;D;D;.;.;.;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.46	.;.;.;T;.;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N;N;.;N;.;N;N
REVEL	Benign	0.045
Sift	Benign	0.64	T;T;T;.;T;.;T;T
Sift4G	Benign	0.50	T;T;T;.;T;.;T;.
Polyphen		0.0	B;B;B;B;.;.;.;.
Vest4		0.063
MutPred		0.69		Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);.;.;Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);
MVP		0.088
MPC		0.049
ClinPred		0.035	T
GERP RS		-5.7
PromoterAI		0.020	Neutral
Varity_R		0.27
gMVP		0.60
Mutation Taster		=95/5	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: rs362129; hg19: chr22-17690409;