rs121908723

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM3_StrongPP1_StrongPP4_ModeratePM2_SupportingPS3_Moderate

This summary comes from the ClinGen Evidence Repository: NM_000022.4 :c.646G>A is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 216 (p.Gly216Arg). The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240). This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt.). 12 individuals were homozygous for the variant (1 pt.) (total: 2 pts; PM3_Strong ,PMID : 26255240). Male patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt.),Increased dATP in pretreatment erythrocytes (2 pts.). (PP4_Moderate (5 pts.), PMID:1680289). ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate). Based on the above evidence, the variant may be classified as pathogenic for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_strong,PM2_supporting,PM3_strong,PP4_moderate,PS3_moderate (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA252008/MONDO:0007064/114

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 6.91

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:

PKIG (HGNC:9019): (cAMP-dependent protein kinase inhibitor gamma) This gene encodes a member of the protein kinase inhibitor family. Studies of a similar protein in mice suggest that this protein acts as a potent competitive cAMP-dependent protein kinase inhibitor, and is a predominant form of inhibitor in various tissues. The encoded protein may be involved in osteogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PKIG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

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

PM2

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

PM3

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

PP1

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

PP4

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.646G>A	p.Gly216Arg	missense_variant	Exon 7 of 12	ENST00000372874.9	NP_000013.2	P00813A0A0S2Z381
ADA	NM_001322050.2 link	c.241G>A	p.Gly81Arg	missense_variant	Exon 6 of 11		NP_001308979.1
ADA	NM_001322051.2 link	c.607-109G>A		intron_variant	Intron 6 of 10		NP_001308980.1	F5GWI4
ADA	NR_136160.2 link	n.738G>A		non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADA	ENST00000372874.9 link	c.646G>A	p.Gly216Arg	missense_variant	Exon 7 of 12	1	NM_000022.4	ENSP00000361965.4	P00813
ADA	ENST00000695995.1 link	c.256G>A	p.Gly86Arg	missense_variant	Exon 4 of 9			ENSP00000512318.1	A0A8Q3SI64
ADA	ENST00000695991.1 link	c.217-109G>A		intron_variant	Intron 3 of 7			ENSP00000512314.1	A0A0S2Z3B9
ADA	ENST00000696038.1 link	n.*392G>A		non_coding_transcript_exon_variant	Exon 7 of 9			ENSP00000512344.1	A0A8Q3SJ57
ADA	ENST00000696038.1 link	n.*392G>A		3_prime_UTR_variant	Exon 7 of 9			ENSP00000512344.1	A0A8Q3SJ57

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251428

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53416

Gnomad4 NFE exome

AF:

0.0000369

AC:

AN:

1111994

Gnomad4 Remaining exome

AF:

0.0000497

AC:

AN:

60392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

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

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000724

AC:

0.0000723764

AN:

0.0000723764

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000735

AC:

0.0000734948

AN:

0.0000734948

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

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:

0.0000930

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other: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

Pathogenic:9Other:1

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the ADA protein (p.Gly216Arg). This variant is present in population databases (rs121908723, gnomAD 0.004%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1346349, 1680289, 9108404, 9758612, 26255240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1968). 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 ADA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 8258146, 9108404, 9758612). For these reasons, this variant has been classified as Pathogenic. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 27, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.646G>A (p.Gly216Arg) in ADA gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the active site of conserved domain and mutations were proven to lead to severe SCID presentation due to complete abolishment of all residual enzyme activity. The variant is present in the large control population dataset of ExAC at a frequency 1.65e-05 (2/121232 chrs tested). The variant has been identified homozygously or in the compound heterozygous state in numerous affected individuals with severe presentation. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -

Mar 29, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 17, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 1991

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 14, 2017

Counsyl

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jan 24, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

NM_000022.4 :c.646G>A is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 216 (p.Gly216Arg). The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240). This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt.). 12 individuals were homozygous for the variant (1 pt.) (total: 2 pts; PM3_Strong ,PMID : 26255240). Male patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt.),Increased dATP in pretreatment erythrocytes (2 pts.). (PP4_Moderate (5 pts.), PMID: 1680289). ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate). Based on the above evidence, the variant may be classified as pathogenic for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_strong,PM2_supporting,PM3_strong,PP4_moderate,PS3_moderate (VCEP specifications version 1). -

not provided

Pathogenic:2

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ADA: PM3:Very Strong, PM2, PS3:Supporting -

Feb 04, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect as this variant impairs ADA function (PMID: 9758612, 8258146); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 9108404, 9758612, 1680289, 28812413, 31589614, 8258146, 32307643, 1346349, 26376800, 33628209, 34539671, 26255240, 27129325, 28747913, 35906326, 33709203) -

ADA-related disorder

Pathogenic:1

Feb 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ADA c.646G>A variant is predicted to result in the amino acid substitution p.Gly216Arg. This variant in the homozygous and compound heterozygous conditions was reported in multiple individuals with adenosine deaminase deficiency/severe combined immunodeficiency (see example: Hirschhorn et al 1991. PubMed ID: 1680289; Mantravadi et al. 2021. PubMed ID: 3453967; Pajno et al. 2020. PubMed ID: 32307643; Verhagen et al. 2020. PubMed ID: 31858364). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

1.0

MutPred

0.97

Gain of MoRF binding (P = 0.0506);

MVP

0.96

MPC

0.69

ClinPred

1.0

GERP RS

4.0

Varity_R

0.98

gMVP

0.98

Mutation Taster

=16/84

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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