rs121908716

Positions:

• chr20-44623053-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP4_Moderate PM2 PS3_Moderate PM3_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000022.4:c.632G>A variant in ADA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 211 (p.Arg211His).The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID:9758612, PS3_moderate). This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met.At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID:9414266). The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Moderate, PM3_Strong, PP1_Strong, PM2_Supporting, PS3_Moderate. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA252000/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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/exons	MANE	Protein	UniProt
ADA	NM_000022.4	c.632G>A	p.Arg211His	missense_variant	7/12	ENST00000372874.9	NP_000013.2
ADA	NM_001322050.2	c.227G>A	p.Arg76His	missense_variant	6/11		NP_001308979.1
ADA	NM_001322051.2	c.607-123G>A		intron_variant			NP_001308980.1
ADA	NR_136160.2	n.724G>A		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.632G>A	p.Arg211His	missense_variant	7/12	1	NM_000022.4	ENSP00000361965	P4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251334 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135854

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461764 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 727182

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R211H in ADA (NM_000022.4) has been reported previously in affected patients (Baffelli 2015 et al). Functional studies demonstrate a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The variant is damaging by in silico prediction tools. The nucleotide c.632 in ADA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 211 of the ADA protein (p.Arg211His). This variant is present in population databases (rs121908716, gnomAD 0.02%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1974554, 9414266, 9758612, 26376800). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1957). 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%. Studies have shown that this missense change alters ADA gene expression (PMID: 9758612). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The NM_000022.4:c.632G>A variant in ADA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 211 (p.Arg211His). The filtering allele frequency (the upper threshold of the 95% CI of 10/35432) of the c.632G>A variant in ADA is 0.0001565 for Latino/Admixed American chromosomes by gnomAD v.2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) and therefore meets this criterion (PM2_Supporting). Total Expressed ADA Activity in SØ3834 in E. coli showed the values: Mean +- SD = 30.4 +- 35.8 (3.0–134.2)[nmol/h/mg protein] and the following percent of Wild Type (Range) = 0.012 - 0.014 (0.001–0.051), belonging to group I of Arredondo-Vega classification, indicating that this variant impacts protein function (PMID: 9758612, PS3_moderate). This variant has been detected in 22 individuals with SCID. Of those individuals, one was a heterozygous compound with c.95+1G>A (variant classified pathogenic according to the SCID VCEP specifications). The trans phase of the variants was confirmed by parental testing (1pt; PMID 9414266). Four individuals were with this variant, and a variant that has not been curated by the SCID VCEP (p.A179D, PMID 26684479; p.R101Q, PMID 16973956; p.Y201*, PMID 26255240, patient #46; p.L107P, PMID 19179314, patient #2) (0pt - These variants will not be curated now because the pathogenic level was already reached). Seventeen individuals were homozygous for the variant (maximum 1pt; PMID 27129325, 20460637, 26376800, 19179314, 16276484, 9758612). 2pts in total, PM3_Strong is met. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome (0.5pt) + Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pt) + ADA-SCID phenotype corrected by ADA gene therapy (1pt), in a total of 4.5 points, which is highly specific for SCID (PP4_Moderate; PMID: 9414266). The variant has been reported to segregate with SCID in 4 affected family members from 2 families (LOD score 2.41; PP1_Strong; PMID 20460637, 26376800). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PP4_Moderate, PM3_Strong, PP1_Strong, PM2_Supporting, PS3_Moderate. (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2016	Variant summary: The ADA c.632G>A (p.Arg211His) variant involves the alteration of a conserved nucleotide. Variant is located at the metal-dependent hydrolase domain and the Adenosine/AMP deaminase domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/121106 control chromosomes at a frequency of 0.0000661, which does not exceed the estimated maximal expected allele frequency of a pathogenic ADA variant (0.001633). This variant has been reported in many ADA deficient patients and functional studies showed that variant leads to enzyme activity deficiency. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 01, 2017	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 20, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 30, 2018	The ADA c.632G>A; p.Arg211His variant has been repeatedly found in patients with ADA deficiency-dependent severe combined immunodeficiency (SCID), including 4 unrelated homozygotes (Arredondo-Vega 1998) and 6 homozygotes from a Romani population, four of whom were related (Baffelli 2015). It has also been reported in the compound heterozygous state, in which this variant was found along with another pathogenic ADA variant, in at least 8 other SCID patients (Arredondo-Vega 1998, Bell 2011, Engel 2007, Onodera 1998). Functional studies have demonstrated that although genes carrying this variant produce full-length mRNA, ADA protein activity is severely reduced or absent (Akeson 1988, Arredondo-Vega 1998). Reduced ADA activity is an established cause of SCID (Hershfield 2003). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 18 out of 277,060 chromosomes), and is classified as pathogenic in ClinVar (ID: 1957). Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.96
MPC		0.70
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.88

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

Other links and lift over

dbSNP: rs121908716; hg19: chr20-43251694;