20-44621103-G-T

Variant names:

• chr20-44621103-G-T
• rs121908718
• NM_000022.4:c.890C>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM1 PM5 PP3_Strong PP5

The NM_000022.4(ADA):​c.890C>A​(p.Pro297Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,020 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003930939: Published functional studies demonstrate a damaging effect as transfection of the mutant cDNA into heterologous cells resulted in expression of a heat-labile ADA of normal electrophoretic mobility, properties exhibited by the ADA in the patients' cells (Hirschhorn et al., 1989)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P297L) has been classified as Likely pathogenic. The gene ADA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:1
• Conservation: PhyloP100: 6.50
• Publications: 7 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

Specifications for ADA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003930939: Published functional studies demonstrate a damaging effect as transfection of the mutant cDNA into heterologous cells resulted in expression of a heat-labile ADA of normal electrophoretic mobility, properties exhibited by the ADA in the patients' cells (Hirschhorn et al., 1989); PMID: 9225964; SCV005345691: Functional studies suggest that this variant impacts ADA function (Hirschhorn et al. 1989. PubMed ID: 2783588; Hirschhorn et al. 1990. PubMed ID: 2166947).; SCV002600454: "Santisteban_2024"
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000022.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44621103-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1505857.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 20-44621103-G-T is Pathogenic according to our data. Variant chr20-44621103-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1961.

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.890C>A	p.Pro297Gln	missense	Exon 10 of 12	NP_000013.2
	ADA	NM_001322051.2		c.818C>A	p.Pro273Gln	missense	Exon 9 of 11	NP_001308980.1	F5GWI4
	ADA	NM_001322050.2		c.485C>A	p.Pro162Gln	missense	Exon 9 of 11	NP_001308979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA	ENST00000372874.9	TSL:1 MANE Select	c.890C>A	p.Pro297Gln	missense	Exon 10 of 12	ENSP00000361965.4	P00813
	ADA	ENST00000537820.2	TSL:1	c.818C>A	p.Pro273Gln	missense	Exon 9 of 11	ENSP00000441818.1	F5GWI4
	ADA	ENST00000695995.1		c.500C>A	p.Pro167Gln	missense	Exon 7 of 9	ENSP00000512318.1	A0A8Q3SI64

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251492 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00118 AC: 18 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000134 Hom.: 0

Bravo AF: 0.000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
2	-	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (3)
1	-	-	ADA-related disorder (1)
1	-	-	Partial adenosine deaminase deficiency (1)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.97		Gain of ubiquitination at K301 (P = 0.0843)
MVP		0.97
MPC		0.54
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.96
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908718; hg19: chr20-43249744;