Genetic Variant NM_001282225.2:c.1078A>G (chr22-17188342-T-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001282225.2(ADA2):c.1078A>G(p.Thr360Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000959 in 1,460,156 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 (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 6.01

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 22-17188342-T-C is Pathogenic according to our data. Variant chr22-17188342-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 189342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA2	NM_001282225.2 link	c.1078A>G	p.Thr360Ala	missense_variant	Exon 7 of 10	ENST00000399837.8	NP_001269154.1	Q9NZK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8 link	c.1078A>G	p.Thr360Ala	missense_variant	Exon 7 of 10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251114

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460156

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 360 of the ADA2 protein (p.Thr360Ala). This variant is present in population databases (rs775440641, gnomAD 0.002%). This missense change has been observed in individual(s) with deficiency of adenosine deaminase 2 (PMID: 12804991, 25075847, 28522451, 30647181). 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. This variant is also known as c.355A>G, p.T119A. ClinVar contains an entry for this variant (Variation ID: 189342). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

See cases

Pathogenic:1

Dec 17, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP1,PP3,PP5 -

Sneddon syndrome

Pathogenic:1

Jul 31, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;D;D;.;D;D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.90

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

MetaSVM

Uncertain

0.56

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0, 1.0

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

Vest4

0.83

MutPred

0.65

.;Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);.;.;

MVP

0.95

MPC

0.31

ClinPred

1.0

GERP RS

3.9

Varity_R

0.98

gMVP

0.76

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

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