20-44625622-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: NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1).This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA266009/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.0037 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 2 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:11O:1

Conservation

PhyloP100: 1.47

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
Omenn syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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.425G>A	p.Arg142Gln	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322051.2 link	c.425G>A	p.Arg142Gln	missense_variant	Exon 5 of 11		NP_001308980.1	F5GWI4
ADA	NR_136160.2 link	n.517G>A		non_coding_transcript_exon_variant	Exon 5 of 11
ADA	NM_001322050.2 link	c.73+834G>A		intron_variant	Intron 4 of 10		NP_001308979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.425G>A	p.Arg142Gln	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000696038.1 link	n.*171G>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 link	n.*171G>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000695995.1 link	c.217-2544G>A		intron_variant	Intron 3 of 8			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.217-2692G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1	A0A0S2Z3B9

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

563

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00101

AC:

204

AN:

202328

AF XY:

0.000681

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000643

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000690

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000431

AC:

617

AN:

1432964

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

266

AN XY:

710034

show subpopulations

African (AFR)

AF:

0.0132

AC:

437

AN:

33006

American (AMR)

AF:

0.000781

AC:

AN:

40982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.0000520

AC:

AN:

38466

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51150

Middle Eastern (MID)

AF:

0.000586

AC:

AN:

5122

European-Non Finnish (NFE)

AF:

0.0000765

AC:

AN:

1097470

Other (OTH)

AF:

0.000979

AC:

AN:

59256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00370

AC:

564

AN:

152306

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0129

AC:

538

AN:

41568

American (AMR)

AF:

0.00111

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0190

Hom.:

2349

Bravo

AF:

0.00440

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00119

AC:

143

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:11Other:1

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

Uncertain:1Benign:6Other:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 10, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1). This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). -

Jan 07, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADA NM_000022.3 exon 5 p.Arg142Gln (c.425G>A): This variant has been reported in the literature in one individual, the unaffected father of a proband with Severe Combined Immunodeficiency (SCID). This variant was not identified in the affected proband, and this proband was reported to carry a different homozygous nonsense mutation (Santisteban 1995 PMID:8589684). This variant is present in 1.3% (276/20894) of African alleles including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-43254263-C-T). This variant is present in ClinVar (Variation ID: 68262). This variant amino acid Glutamine (Gln) is present in 9 species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest a reduction in ADA activity vs. wild type with literature suggesting this may be a "partial" variant; however, these studies may not accurately represent in vivo biological function (Santisteban 1995 PMID:8589684, Arredondo-Vega 1998 PMID:9758612).In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 23, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R142Q variant in the ADA gene has been reported previously, along with another variant, in the unaffected father of a Somali child with SCID who was homozygous for a nonsense variant in the ADA gene (Santisteban et al., 1995). The R142Q variant is observed in 265/19952 (1.3%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The R142Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In vitro function studies showed the R142Q variant reduced ADA enzyme activity between 42.8-80% compared to wild type (Richard et al., 2002; Santisteban et al., 1995). We interpret R142Q as a variant of uncertain significance. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ADA c.425G>A (p.Arg142Gln) results in a conservative amino acid change located in the Adenosine deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 202328 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADA causing Severe Combined Immunodeficiency phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.425G>A has been reported in the literature in an unaffected compound heterozygous (Q3X/R142Q) individual with an affected child who was homozygous for Q3X (Santisteban_1995). Two studies have demonstrated this variant partially reduce enzyme activity in vitro (Santisteban_1995 and Arredono-Vega_1998). Additionally, Richard_2000 demonstrated that recombinant human ADA bearing the R142Q mutation impaired binding to a CD26+ ADA-deficient human T cell line. These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=4), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

ADA-related disorder

Benign:1

Aug 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Benign

0.094

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;D

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0086

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.5

L;.

PhyloP100

1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.25

Sift

Benign

0.47

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.024

B;.

Vest4

0.39

MVP

0.84

MPC

0.17

ClinPred

0.015

GERP RS

-0.31

Varity_R

0.087

gMVP

0.43

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over