rs121908715

Variant names:

• chr20-44620391-G-A
• rs121908715
• NM_000022.4:c.986C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-44620391-G-A
• chr20-44620391-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM6 PP4_Moderate PM3_Strong PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.986C>T (NM_000022.4) variant in ADA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 329 (p.Ala329Val).The filtering allele frequency (the upper threshold of the 95% CI of 37/74910) of the c.986C>T variant in ADA is 0.0003683 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore do not meet this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.In vitro experiments of ADA activity in E. coli demonstrated a percentage of wild-type (wt) activity ranging from 0.1% to 5.1%, with an average ± standard deviation of 1.2% ± 1.4%. This finding classifies the variant into Group I, suggesting a significant impact on protein function. (PS3_Moderate; PMID 9758612).This variant has been detected in many individuals in the literature. Evaluated here four patients with ADA-SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant: * PMID 8614422, compound heterozygous with p.Gly74Val (at least likely pathogenic according to SCID VCEP specifications, Phase is not confirmed = 0.25pt;* PMID 32307643, compound heterozygous with p.Ser291Leu (at least likely pathogenic according to SCID VCEP specifications. Phase is not confirmed = 0.25pt;* PMID:8401541, Proband 1 is comp. het. A329V and Q254X (at least likely pathogenic according to SCID VCEP specifications - PM2_Supporting and PVS1) - phase (in trans) confirmed = 1pt; Additionally, 01 individual was homozygous for the variant = 0.5 pts (PMID:1346349). The total is 2 points, PM3_Strong.Patient from PMID 8614422 presented: * ADA activity in patient RBCs was undetectable (1pt), * Concentration of total deoxyadenosine nucleotides was elevated (2pt). * ADA-SCID phenotypes of the patient were corrected by PEG-ADA supplement (1pt). Total = 4 points, PP4_Moderate. PMID:8614422.This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 01 individual with ADA-SCID, with phenotype highly specific for the gene (PM6_Moderate, PMID:1346349).In summary, this variant is classified as Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PS3_Moderate, PM3_Strong, PP4_Moderate, and PM6_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA252004/MONDO:0007064/114

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 8.32
• Publications: 9 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 11 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.
• PM6: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	NM_000022.4	MANE Select	c.986C>T	p.Ala329Val	missense	Exon 11 of 12	NP_000013.2
	ADA	NM_001322051.2		c.914C>T	p.Ala305Val	missense	Exon 10 of 11	NP_001308980.1
	ADA	NM_001322050.2		c.581C>T	p.Ala194Val	missense	Exon 10 of 11	NP_001308979.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.986C>T	p.Ala329Val	missense	Exon 11 of 12	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.914C>T	p.Ala305Val	missense	Exon 10 of 11	ENSP00000441818.1
	ADA	ENST00000695995.1		c.596C>T	p.Ala199Val	missense	Exon 8 of 9	ENSP00000512318.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251486 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727202

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111938

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74352

African (AFR) AF: 0.000652 AC: 27 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (9)
4	-	-	not provided (4)
1	-	-	ADA-related disorder (1)
1	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		8.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.95
MPC		0.61
ClinPred		0.79	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.94
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121908715; hg19: chr20-43249032;