chr22-17209539-C-G

Position:

chr22-17209539-C-G

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001282225.2(ADA2):c.139G>C(p.Gly47Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,982 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. 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: 0.000023 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.43

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 26 ACMG points.

PS1

Transcript NM_001282225.2 (ADA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 120304

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, 0.989

PP5

Variant 22-17209539-C-G is Pathogenic according to our data. Variant chr22-17209539-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1076271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2 linkuse as main transcript	c.139G>C	p.Gly47Arg	missense_variant	2/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8 linkuse as main transcript	c.139G>C	p.Gly47Arg	missense_variant	2/10	1	NM_001282225.2	P1	Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251330

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

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:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 47 of the ADA2 protein (p.Gly47Arg). This variant is present in population databases (rs202134424, gnomAD 0.01%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 24552285, 24737293, 25075844, 27059682, 28522451, 28830446, 31008556, 31291964). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1076271). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ADA2: PM3:Strong, PS1, PM1, PM2, PM5 -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Autoinflammatory syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 06, 2021

- -

ADA2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

The ADA2 c.139G>C variant is predicted to result in the amino acid substitution p.Gly47Arg. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with ADA2-related disease (see for example - Nanthapisal et al. 2016. PubMed ID: 27059682; Skrabl-Baumgartner et al. 2017. PubMed ID: 28830446). Functional studies found this variant results in <20% of wild type activity (Jee et al. 2021. PubMed ID: 34004258). Additionally, an alternate nucleotide substitution (c.139G>A) resulting in the same missense variant and alternate missense variants affecting this residue (p.Gly47Trp, p.Gly47Ala, p.Gly47Val) have been reported as pathogenic (Karacan et al. 2019. PubMed ID: 30783801; Jee et al. 2021. PubMed ID: 34004258). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-17690429-C-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D;D;.;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;.;.;T;.;T;T;T

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.20

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.7

D;D;D;.;D;.;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;.;D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;.;D;.;D;.

Polyphen

1.0

D;D;D;D;.;.;.;.

Vest4

0.93

MutPred

0.81

Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);.;.;Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);

MVP

0.78

MPC

0.33

ClinPred

0.96

GERP RS

4.8

Varity_R

0.96

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over