20-44651586-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_SupportingBA1

This summary comes from the ClinGen Evidence Repository: The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA115289/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.045 ( 244 hom., cov: 32)

Exomes 𝑓: 0.057 ( 2797 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:10

Conservation

PhyloP100: -0.538

Variant links:

Genes affected

ADA (HGNC:186): (adenosine deaminase) This gene encodes an enzyme that catalyzes the hydrolysis of adenosine to inosine in the purine catabolic pathway. Various mutations have been described for this gene and have been linked to human diseases related to impaired immune function such as severe combined immunodeficiency disease (SCID) which is the result of a deficiency in the ADA enzyme. In ADA-deficient individuals there is a marked depletion of T, B, and NK lymphocytes, and consequently, a lack of both humoral and cellular immunity. Conversely, elevated levels of this enzyme are associated with congenital hemolytic anemia. [provided by RefSeq, Sep 2019]

ADA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4 link	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 11		NP_001308980.1	F5GWI4
ADA	NM_001322050.2 link	c.-268G>A		5_prime_UTR_variant	Exon 1 of 11		NP_001308979.1
ADA	NR_136160.2 link	n.114G>A		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 link	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 9			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.22G>A	p.Asp8Asn	missense_variant	Exon 1 of 8			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 link	n.22G>A		non_coding_transcript_exon_variant	Exon 1 of 9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6871

AN:

151866

Hom.:

246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0346

Gnomad ASJ

AF:

0.0931

Gnomad EAS

AF:

0.0542

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.0608

Gnomad MID

AF:

0.0828

Gnomad NFE

AF:

0.0568

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0621

AC:

8711

AN:

140254

AF XY:

0.0691

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0258

Gnomad ASJ exome

AF:

0.0945

Gnomad EAS exome

AF:

0.0540

Gnomad FIN exome

AF:

0.0618

Gnomad NFE exome

AF:

0.0535

Gnomad OTH exome

AF:

0.0600

GnomAD4 exome

AF:

0.0573

AC:

79583

AN:

1388672

Hom.:

2797

Cov.:

AF XY:

0.0602

AC XY:

41370

AN XY:

686784

show subpopulations

Gnomad4 AFR exome

AF:

0.00952

AC:

296

AN:

31096

Gnomad4 AMR exome

AF:

0.0263

AC:

979

AN:

37178

Gnomad4 ASJ exome

AF:

0.0937

AC:

2347

AN:

25052

Gnomad4 EAS exome

AF:

0.0401

AC:

1439

AN:

35876

Gnomad4 SAS exome

AF:

0.130

AC:

10378

AN:

79894

Gnomad4 FIN exome

AF:

0.0670

AC:

2297

AN:

34260

Gnomad4 NFE exome

AF:

0.0532

AC:

57618

AN:

1082936

Gnomad4 Remaining exome

AF:

0.0637

AC:

3686

AN:

57834

Heterozygous variant carriers

3875

7751

11626

15502

19377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

2190

4380

6570

8760

10950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0452

AC:

6862

AN:

151974

Hom.:

244

Cov.:

AF XY:

0.0462

AC XY:

3430

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0102

AC:

0.0101741

AN:

0.0101741

Gnomad4 AMR

AF:

0.0346

AC:

0.0345685

AN:

0.0345685

Gnomad4 ASJ

AF:

0.0931

AC:

0.0931373

AN:

0.0931373

Gnomad4 EAS

AF:

0.0542

AC:

0.0542169

AN:

0.0542169

Gnomad4 SAS

AF:

0.127

AC:

0.126714

AN:

0.126714

Gnomad4 FIN

AF:

0.0608

AC:

0.0608351

AN:

0.0608351

Gnomad4 NFE

AF:

0.0568

AC:

0.0567814

AN:

0.0567814

Gnomad4 OTH

AF:

0.0545

AC:

0.0544508

AN:

0.0544508

Heterozygous variant carriers

324

649

973

1298

1622

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0556

Hom.:

Bravo

AF:

0.0400

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0566

AC:

218

ESP6500AA

AF:

0.00717

AC:

ESP6500EA

AF:

0.0419

AC:

286

ExAC

AF:

0.0343

AC:

3458

Asia WGS

AF:

0.0750

AC:

261

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency

Benign:7

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000022.2:c.22G>A variant in ADA is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 8 (p.Asp8Asn). This variant is present at an overall minor allele frequency of 0.05863 (10050/171418 alleles) with the highest population minor allele frequency of 0.1300 (3033/23322) in the South Asian population in gnomAD v2.1.1. This frequency is higher than the ClinGen SCID VCEP's threshold for BA1 (>0.00721); therefore, BA1 is met. This variant has been observed in 434 homozygous individuals in gnomAD, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29191167, 16221767, 20414589, 22952909, 18794722, 11354825, 24896148, 21734253, 17287605, 20174870, 8031011) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Adenosine deaminase 2 allozyme

Pathogenic:1

Mar 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Jan 09, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.60

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

-0.91

N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

0.28

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.86

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.071

MPC

0.14

ClinPred

0.017

GERP RS

-1.4

Varity_R

0.44

gMVP

0.44

Mutation Taster

=99/1

polymorphism (auto)

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