20-44621103-G-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
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).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
ADA
NM_000022.4 missense
NM_000022.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.50
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
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 id is 1961.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1, not_provided=1}. Variant chr20-44621103-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.890C>A | p.Pro297Gln | missense_variant | Exon 10 of 12 | ENST00000372874.9 | NP_000013.2 | |
ADA | NM_001322051.2 | c.818C>A | p.Pro273Gln | missense_variant | Exon 9 of 11 | NP_001308980.1 | ||
ADA | NM_001322050.2 | c.485C>A | p.Pro162Gln | missense_variant | Exon 9 of 11 | NP_001308979.1 | ||
ADA | NR_136160.2 | n.917C>A | non_coding_transcript_exon_variant | Exon 9 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.890C>A | p.Pro297Gln | missense_variant | Exon 10 of 12 | 1 | NM_000022.4 | ENSP00000361965.4 | ||
ADA | ENST00000695995.1 | c.500C>A | p.Pro167Gln | missense_variant | Exon 7 of 9 | ENSP00000512318.1 | ||||
ADA | ENST00000695991.1 | c.428C>A | p.Pro143Gln | missense_variant | Exon 6 of 8 | ENSP00000512314.1 | ||||
ADA | ENST00000695956.1 | c.44C>A | p.Pro15Gln | missense_variant | Exon 1 of 3 | ENSP00000512285.1 | ||||
ADA | ENST00000696038.1 | n.*647C>A | non_coding_transcript_exon_variant | Exon 8 of 9 | ENSP00000512344.1 | |||||
ADA | ENST00000696038.1 | n.*647C>A | 3_prime_UTR_variant | Exon 8 of 9 | ENSP00000512344.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251492Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135918
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727236
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2024 | 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, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2023 | 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) - |
Partial adenosine deaminase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1989 | - - |
ADA-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2022 | Variant summary: ADA c.890C>A (p.Pro297Gln) results in a non-conservative amino acid change located in the Adenosine deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251492 control chromosomes (gnomAD). c.890C>A has been reported in the literature in the homozygous and compound heterozygous states in two partially ADA deficient children, identified through Newborn Screening (Hirschhorn_1989, Hirschhorn_1990). A later report by the same authors (Hirschhorn_1995) stated that up to that date, the children had not presented with immunodeficiency. GeneReviews defines partial ADA deficiency as a benign condition which is compatible with normal immune function (PMID 20301656). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Experimental evidence evaluating an impact on protein function demonstrated the variant to have normal electrophoretic mobility and abnormal heat stability, with ADA activity measured at 56% in homozygous lymphoid cells (Hirschhorn_1989, Hirschhorn_1990). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MutPred
Gain of ubiquitination at K301 (P = 0.0843);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at