rs146597836

Positions:

chr22-17189987-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001282225.2(ADA2):c.927G>A(p.Met309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:8

Conservation

PhyloP100: 1.07

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:

ADA2 (HGNC:):

ADA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004589975).

BP6

Variant 22-17189987-C-T is Benign according to our data. Variant chr22-17189987-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375247.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr22-17189987-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00154 (2255/1461760) while in subpopulation MID AF= 0.012 (69/5766). AF 95% confidence interval is 0.0097. There are 4 homozygotes in gnomad4_exome. There are 1196 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2 linkuse as main transcript	c.927G>A	p.Met309Ile	missense_variant	6/10	ENST00000399837.8	NP_001269154.1	Q9NZK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8 linkuse as main transcript	c.927G>A	p.Met309Ile	missense_variant	6/10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00175

AC:

441

AN:

251468

Hom.:

AF XY:

0.00185

AC XY:

252

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.00358

GnomAD4 exome

AF:

0.00154

AC:

2255

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1196

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00161

Gnomad4 ASJ exome

AF:

0.00517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00215

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152322

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00173

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00198

AC:

240

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ADA2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 19, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2018	The p.Met309Ile variant in ADA2 is classified as benign because of its high frequency of 0.61% in Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146597836). This variant is present in ClinVar (variant ID 361951). Computational prediction tools and conservation analysis suggest that the p.Met309Ile variant may not impact the protein. ACMG/AMP criteria applied: BA1, BP4. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2022	- -

Behcet disease

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Department of Immunology, Hospital Universitario Virgen del Rocio

Jan 13, 2017

- -

Vasculitis due to ADA2 deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 17, 2022

- -

ADA2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

9.5

DANN

Benign

0.70

DEOGEN2

Benign

0.024

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.57

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

M_CAP

Benign

0.059

MetaRNN

Benign

0.0046

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.55

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

.;N;N;N;N;.;N;.

REVEL

Uncertain

0.29

Sift

Benign

0.43

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

Sift4G

Benign

0.59

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

Polyphen

0.0020, 0.0

.;B;B;B;B;B;.;.

Vest4

0.29

MutPred

0.71

.;Loss of MoRF binding (P = 0.1393);Loss of MoRF binding (P = 0.1393);.;Loss of MoRF binding (P = 0.1393);Loss of MoRF binding (P = 0.1393);.;.;

MVP

0.71

MPC

0.048

ClinPred

0.0025

GERP RS

2.9

Varity_R

0.26

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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