rs1555843178
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000022.4(ADA):c.1078+2T>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
NM_000022.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.1078+2T>A | splice_donor_variant | ENST00000372874.9 | |||
ADA | NM_001322050.2 | c.673+2T>A | splice_donor_variant | ||||
ADA | NM_001322051.2 | c.1006+2T>A | splice_donor_variant | ||||
ADA | NR_136160.2 | n.1105+2T>A | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.1078+2T>A | splice_donor_variant | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461310Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727030
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 23, 2024 | The c.1078+2T>A (NM_000022.4) variant in ADA occurs within the canonical splice donor site (+2) of intron 11. It is predicted to cause skipping of biologically relevant exon by SpliceAI (Δ score = Donor Loss = 0.97); however, due to the location, it is NOT predicted to undergo NMD. There aren't known downstream pathogenic variants; PVS1_Moderate. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient present: Reduced ADA enzyme activity in patient cells (1pt) + Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), reaching 3 points, PP4_Moderate. This variant has been detected in 02 individuals with ADA SCID. One of them is compound heterozygous with c.955-958delGAAG, p.E320RfsX6, a frameshift termination, which is at least LP according to SCID VCEP. Phase is unknown, so 0.5 pt; The second one is compound heterozygous, for c.482G > A, p.W161X (Also at least LP according to SCID VCEP). Phase is not shown. 0.5pts. Total is 1 pt, PM3_Moderate (PMIDs: 32307643 and 26255240). In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PVS1_Strong, PP4_Moderate, and PM3_Moderate. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 14, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at