rs146597836

chr22-17189987-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M309T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: 1.07

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 Benign. Variant got -9 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=3, Benign=2, Uncertain_significance=1}. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADA2	NM_001282225.2	c.927G>A	p.Met309Ile	missense_variant	6/10	ENST00000399837.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADA2	ENST00000399837.8	c.927G>A	p.Met309Ile	missense_variant	6/10	1	NM_001282225.2	P1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152204 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.00185 AC XY: 252 AN XY: 135906

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.: 4 Cov.: 30 AF XY: 0.00164 AC XY: 1196 AN XY: 727200

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.: 0 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74480

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.: 0

Bravo AF: 0.00173

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADA2: BS2 -
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	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 19, 2017	- -

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

Invitae

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, criteria provided, single submitter

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	T
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	D
LIST_S2	Benign	0.57	T;.;.;T;.;T;.;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0046	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Benign	0.36	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	T
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

Other links and lift over

dbSNP: rs146597836; hg19: chr22-17670877;