22-17203587-C-T

Position:

chr22-17203587-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001282225.2(ADA2):c.729G>A(p.Met243Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,612,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ADA2
NM_001282225.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.443

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12817961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2 linkuse as main transcript	c.729G>A	p.Met243Ile	missense_variant	4/10	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.729G>A	p.Met243Ile	missense_variant	4/10	1	NM_001282225.2	ENSP00000382731.2		Q9NZK5-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152198

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251332

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1460410

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726538

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:

0.0000567

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Vasculitis due to ADA2 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2022

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 243 of the ADA2 protein (p.Met243Ile). This variant is present in population databases (rs151014930, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ADA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 541734). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.0025

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

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.035

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

-0.17

PrimateAI

Benign

0.34

PROVEAN

Benign

0.040

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

REVEL

Benign

0.26

Sift

Benign

0.53

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

Sift4G

Benign

0.91

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

Polyphen

0.0010

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

Vest4

0.27

MutPred

0.59

.;Loss of phosphorylation at Y242 (P = 0.0842);Loss of phosphorylation at Y242 (P = 0.0842);Loss of phosphorylation at Y242 (P = 0.0842);Loss of phosphorylation at Y242 (P = 0.0842);.;.;

MVP

0.73

MPC

0.048

ClinPred

0.044

GERP RS

3.6

Varity_R

0.33

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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