rs1555844395
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000022.4(ADA):c.603C>G(p.Tyr201Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,990 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y201Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000022.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADA | NM_000022.4 | c.603C>G | p.Tyr201Ter | stop_gained | 6/12 | ENST00000372874.9 | |
ADA | NM_001322051.2 | c.603C>G | p.Tyr201Ter | stop_gained | 6/11 | ||
ADA | NM_001322050.2 | c.198C>G | p.Tyr66Ter | stop_gained | 5/11 | ||
ADA | NR_136160.2 | n.695C>G | non_coding_transcript_exon_variant | 6/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADA | ENST00000372874.9 | c.603C>G | p.Tyr201Ter | stop_gained | 6/12 | 1 | NM_000022.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1458990Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725600
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
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Jan 24, 2024 | The c.603C>G (p.Tyr201Ter) (NM_000022.4) variant in ADA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/12 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The highest population minor allele frequency in gnomAD v4 is 0.00002992 (1/33422 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). There are no publications for this variant in the literature. Patient # 46 was found to be heterozygous for c.603C>G (p.Tyr201*) and c.632G>A (p.Arg211His) which is classified as pathogenic for SCID by the ClinGen SCID VCEP (1 pt.) (PMID: 26255240, PM3). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PM3,PVS1 (VCEP specifications version 1). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at