rs121908716

Variant names:

• chr20-44623053-C-T
• rs121908716
• NM_000022.4:c.632G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-44623053-C-T
• chr20-44623053-C-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1_Strong PP4_Moderate PM2 PM3_Strong PS3_Moderate

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:13 O:1
• Conservation: PhyloP100: 6.91
• Publications: 13 publications found

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

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000022.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.632G>A	p.Arg211His	missense	Exon 7 of 12	NP_000013.2
	ADA	NM_001322050.2		c.227G>A	p.Arg76His	missense	Exon 6 of 11	NP_001308979.1
	ADA	NM_001322051.2		c.607-123G>A		intron	N/A	NP_001308980.1	F5GWI4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.632G>A	p.Arg211His	missense	Exon 7 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000695995.1		c.242G>A	p.Arg81His	missense	Exon 4 of 9	ENSP00000512318.1	A0A8Q3SI64
	ADA	ENST00000537820.2	TSL:1	c.607-123G>A		intron	N/A	ENSP00000441818.1	F5GWI4

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

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251334 AF XY: 0.0000736

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 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

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111930

Other (OTH) AF: 0.000116 AC: 7 AN: 60382

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

African (AFR) AF: 0.000169 AC: 7 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000865 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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (12)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.9
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
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908716; hg19: chr20-43251694;