20-44621103-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P297L) has been classified as Likely pathogenic.

• 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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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

Selected	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
	ADA	NM_001322050.2		c.485C>A	p.Pro162Gln	missense	Exon 9 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.890C>A	p.Pro297Gln	missense	Exon 10 of 12	ENSP00000361965.4
	ADA	ENST00000537820.2	TSL:1	c.818C>A	p.Pro273Gln	missense	Exon 9 of 11	ENSP00000441818.1
	ADA	ENST00000695995.1		c.500C>A	p.Pro167Gln	missense	Exon 7 of 9	ENSP00000512318.1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:2 Other:1

Mar 25, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 297 of the ADA protein (p.Pro297Gln). This variant is present in population databases (rs121908718, gnomAD 0.02%). This missense change has been observed in individual(s) with partial adenosine deaminase (ADA) deficiency (PMID: 2166947, 2783588). ClinVar contains an entry for this variant (Variation ID: 1961). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ADA function (PMID: 2166947). This variant disrupts the p.Pro297 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1 Uncertain:1

May 09, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9225964, 2783588, 21898656, 24772956, 20493397, 2166947, 31589614, 34975878, 23645737)

Oct 21, 2025

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.890C>A (p.Pro297Gln) variant has been reported in the homozygous and compound heterozygous state in two unrelated children with “partial ADA deficiency” ascertained by newborn screening in New York. The affected children's families were both reported to be from Santo Domingo, but were not known to be related. No clinical information was provided for either child (PMID:2783588). This variant has also been reported in a large cohort undergoing preconception carrier screening, however although it was classified as pathogenic in this publication, evidence to support the pathogenic classification was not provided (PMID:31589614). Functional studies have been performed that indicate that this variant results in a decrease in ADA activity at 28% of wild type (PMID:2166947; PMID:39182630). This activity level falls into expression group IV, which includes variants found in healthy individuals or those with only partial ADA deficiency, and is not expected to cause severe ADA deficiency (PMID:9758612). The overall minor allele frequency for this variant (rs121908718) is approximately 0.003% with a frequency up to 0.02% in Latino/Admixed American sub-populations. There is a moderate physicochemical difference between proline and glutamine. This amino acid is moderately conserved across species. Taken together, this variant likely results in partial ADA deficiency; however, even when present in trans (on the opposite allele) with a severe pathogenic variant, the residual ADA activity is not expected to be low enough to cause a disease phenotype. The possibility of further reduction in ADA activity due to other contributing variables cannot be entirely excluded. Therefore, this variant is classified as a variant of uncertain significance. Criteria: PM3_Mod, PM2_Sup, PM5_Sup, PS3_Sup

Partial adenosine deaminase deficiency Pathogenic:1

Feb 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

ADA-related disorder Pathogenic:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ADA c.890C>A variant is predicted to result in the amino acid substitution p.Pro297Gln. This variant has been reported in the homozygous and compound heterozygous states in individuals with partial adenosine deaminase (ADA) deficiency (Hirschhorn et al. 1989. PubMed ID: 2783588; Hirschhorn et al. 1990. PubMed ID: 2166947). Functional studies suggest that this variant impacts ADA function (Hirschhorn et al. 1989. PubMed ID: 2783588; Hirschhorn et al. 1990. PubMed ID: 2166947). Of note, another variant impacting the same amino acid [c.890C>T (p.Pro297Leu)] was reported in the compound heterozygous state in an individual with predominantly antibody deficiency (Patient P221, Rojas-Restrepo. 2021. PubMed ID: 34975878). The c.890C>A (p.Pro297Gln) variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar regarding its pathogenicity, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/1961/). Taken together, this variant is interpreted as likely pathogenic.

Severe combined immunodeficiency disease Pathogenic:1

May 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADA c.890C>A (p.Pro297Gln) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2.8e-05 in 251492 control chromosomes (gnomAD). The variant, c.890C>A, has been observed in two children with partial adenosine deaminase (ADA) deficiency identified through Newborn Screening, who presented with no ADA activity in their erythrocytes (RBCs), but had ~28% derived residual ADA activity in their EBV-immortalized lymphoid cell lines (Hirschhorn_1989, Hirschhorn_1990). In a later report the same author(s) stated that up to that date the children had not presented with immunodeficiency (Hirschhorn_1995). However, the variant was later reported in a different patient who had late-onset ADA deficiency (diagnosed at the age of 37yo) with an immunologic phenotype that is consistent with a milder disease (Zhang_2023). At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating that Pro297Gln decreased enzyme activity in an in vitro expression system (Santisteban_2024). In addition, a different missense affecting the same amino acid (p.Pro297Leu) is classified as Likely Pathogenic by our lab and others, including the ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel [Variation ID 1505857], suggesting the critical importance of the affected residue. The following publications have been ascertained in the context of this evaluation (PMID: 7554472, 2783588, 2166947, 37154862, 39182630). ClinVar contains an entry for this variant (Variation ID: 1961). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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;