rs1555844600
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_000022.4(ADA):c.478+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
ADA
NM_000022.4 splice_donor_region, intron
NM_000022.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9987
2
Clinical Significance
Conservation
PhyloP100: 3.12
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 20-44625563-A-G is Pathogenic according to our data. Variant chr20-44625563-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 624615.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.478+6T>C | splice_donor_region_variant, intron_variant | ENST00000372874.9 | |||
ADA | NM_001322050.2 | c.73+893T>C | intron_variant | ||||
ADA | NM_001322051.2 | c.478+6T>C | splice_donor_region_variant, intron_variant | ||||
ADA | NR_136160.2 | n.570+6T>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.478+6T>C | splice_donor_region_variant, intron_variant | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 7.04e-7 AC: 1AN: 1420502Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 702836
GnomAD4 exome
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1420502
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31
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0
AN XY:
702836
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
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:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the ADA gene. It does not directly change the encoded amino acid sequence of the ADA protein. It affects a nucleotide within the consensus splice site. This variant has been observed in individual(s) with severe combined immunodeficiency (PMID: 31031743). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.478+6 nucleotide in the ADA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8227344, 33628209). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
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: 6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at