Menu
GeneBe

rs121908723

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000022.4(ADA):c.646G>A(p.Gly216Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,614,040 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. G216G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ADA
NM_000022.4 missense

Scores

13
5
1

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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a strand (size 9) in uniprot entity ADA_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000022.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 20-44623039-C-T is Pathogenic according to our data. Variant chr20-44623039-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1968.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr20-44623039-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADANM_000022.4 linkuse as main transcriptc.646G>A p.Gly216Arg missense_variant 7/12 ENST00000372874.9
ADANM_001322050.2 linkuse as main transcriptc.241G>A p.Gly81Arg missense_variant 6/11
ADANM_001322051.2 linkuse as main transcriptc.607-109G>A intron_variant
ADANR_136160.2 linkuse as main transcriptn.738G>A non_coding_transcript_exon_variant 7/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADAENST00000372874.9 linkuse as main transcriptc.646G>A p.Gly216Arg missense_variant 7/121 NM_000022.4 P4

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152180
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251428
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135890
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461860
Hom.:
0
Cov.:
33
AF XY:
0.0000303
AC XY:
22
AN XY:
727234
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:
0.0000369
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000724
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000107
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000165
AC:
2
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
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 29, 2019This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCounsylFeb 14, 2017- -
Pathogenic, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenJan 24, 2024NM_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). -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 27, 2017Variant 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. -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 1991- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 17, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 28, 2023This 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024ADA: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 10, 2017The G216R missense variant in the ADA gene has been reported previously in association with adenosine adeaminase deficiency in patients of varied ancestries (Hirschhorn et al., 1991; Arredondo-Vega et al., 1998; Adams et al., 2015; Baffelli et al., 2015). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G216R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R211H/C, V213F, A215T, E217K) have been reported in the Human Gene Mutation Database in association with ADA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, functional studies have shown that the G216R variant results in reduced catalytic activity and early clinical presentation of the disorder (Arredondo-Vega et al., 1998). Therefore, we consider this variant to be pathogenic. -
ADA-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 29, 2024The 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
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
30
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
1.0
MutPred
0.97
Gain of MoRF binding (P = 0.0506);
MVP
0.96
MPC
0.69
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.98
gMVP
0.98

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.

Other links and lift over

dbSNP: rs121908723; hg19: chr20-43251680; API