rs761242509
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000022.4(ADA):c.478+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,575,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000061 ( 0 hom. )
Consequence
ADA
NM_000022.4 splice_donor, intron
NM_000022.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.54
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-44625568-C-T is Pathogenic according to our data. Variant chr20-44625568-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ADA | NM_000022.4 | c.478+1G>A | splice_donor_variant, intron_variant | ENST00000372874.9 | NP_000013.2 | |||
| ADA | NM_001322051.2 | c.478+1G>A | splice_donor_variant, intron_variant | NP_001308980.1 | ||||
| ADA | NM_001322050.2 | c.73+888G>A | intron_variant | NP_001308979.1 | ||||
| ADA | NR_136160.2 | n.570+1G>A | splice_donor_variant, intron_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ADA | ENST00000372874.9 | c.478+1G>A | splice_donor_variant, intron_variant | 1 | NM_000022.4 | ENSP00000361965.4 | ||||
| ADA | ENST00000695995.1 | c.217-2490G>A | intron_variant | ENSP00000512318.1 | ||||||
| ADA | ENST00000695991.1 | c.217-2638G>A | intron_variant | ENSP00000512314.1 | ||||||
| ADA | ENST00000696038.1 | n.*224+1G>A | splice_donor_variant, intron_variant | ENSP00000512344.1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000206 AC: 4AN: 193792Hom.: 0 AF XY: 0.0000289 AC XY: 3AN XY: 103752
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GnomAD4 exome AF: 0.0000611 AC: 87AN: 1423636Hom.: 0 Cov.: 31 AF XY: 0.0000568 AC XY: 40AN XY: 704604
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GnomAD4 genome 0.0000263 AC: 4AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
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:7
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2023 | This sequence change affects a donor splice site in intron 5 of the ADA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with adenosine deaminase deficiency (PMID: 7599635, 8673127). This variant is also known as c.573+1G>A and IVS5+1GT>AT. ClinVar contains an entry for this variant (Variation ID: 265025). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 26, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0210 - Canonical splice site variant proven to affect splicing of the transcript with a known effect on protein structure. This variant is located in intron 5 of 11 and has been shown to cause skipping of exon 5, resulting in a frameshift deletion and nonsense-mediated decay (NMD) (PMID: 7599635). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals with severe combined immunodeficiency due to ADA deficiency (ClinVar, PMID: 7599635, PMID: 8673127, PMID: 22968453, PMID: 31858364) . (P) 1002 - Moderate functional evidence supporting abnormal protein function as shown that ADA activity was reduced compared to wild-type and carriers (PMID: 8673127). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 27, 2021 | NM_000022.2(ADA):c.478+1G>A is a canonical splice variant classified as pathogenic in the context of adenosine deaminase deficiency. c.478+1G>A has been observed in cases with relevant disease (PMID: 7599635, 22968453). Functional assessments of this variant are available in the literature (PMID: 7599635). c.478+1G>A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.478+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 11, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1996 | - - |
Severe combined immunodeficiency disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2020 | Variant summary: ADA c.478+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing and results in deletion of exon 5 (Santisteban_1995, Hirschhorn_1996). The variant allele was found at a frequency of 2.1e-05 in 193792 control chromosomes (gnomAD). c.478+1G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (Santisteban_1995, Hirschhorn_1996, Gaspar_2011). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2017 | The c.478+1 G>A splice site variant in the ADA gene has been previously reported in association with adenosine deaminase deficiency (Santisteban et al., 1995; Grunebaum et al., 2012). This pathogenic variant destroys the canonical splice donor site in intron 5, and has been shown to cause abnormal gene splicing (Santisteban et al., 1995). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at