Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000022.4(ADA):c.606+1G>T

CA409120729

1901446 (ClinVar)

Gene: ADA
Condition: adenosine deaminase deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: e9d7eb13-9877-4191-a288-796b4861ce6b
Approved on: 2024-06-19
Published on: 2024-06-19

HGVS expressions

NM_000022.4:c.606+1G>T
NM_000022.4(ADA):c.606+1G>T
NC_000020.11:g.44624201C>A
CM000682.2:g.44624201C>A
NC_000020.10:g.43252842C>A
CM000682.1:g.43252842C>A
NC_000020.9:g.42686256C>A
NG_007385.1:g.32535G>T
ENST00000492931.6:n.697+1G>T
ENST00000536076.2:c.453+1G>T
ENST00000536532.6:c.606+1G>T
ENST00000537820.2:c.606+1G>T
ENST00000539235.6:c.219-1123G>T
ENST00000695889.1:c.219-1271G>T
ENST00000695890.1:n.2409+1G>T
ENST00000695891.1:c.219-1271G>T
ENST00000695927.1:c.684+1G>T
ENST00000695949.1:c.603+1G>T
ENST00000695957.1:c.*97+1G>T
ENST00000695991.1:c.217-1271G>T
ENST00000695992.1:c.606+1G>T
ENST00000695993.1:c.606+1G>T
ENST00000695994.1:c.606+1G>T
ENST00000695995.1:c.217-1123G>T
ENST00000695996.1:n.677+1G>T
ENST00000695997.1:n.562G>T
ENST00000696003.1:n.698+1G>T
ENST00000696004.1:n.698+1G>T
ENST00000696005.1:c.128+1G>T
ENST00000696006.1:c.606+1G>T
ENST00000696007.1:c.457+1G>T
ENST00000696008.1:n.1762G>T
ENST00000696009.1:n.1957G>T
ENST00000696017.1:c.603+1G>T
ENST00000696034.1:c.606+1G>T
ENST00000696035.1:n.716+1G>T
ENST00000696036.1:n.1296+1G>T
ENST00000696037.1:n.2283+1G>T
ENST00000696038.1:c.*352+1G>T
ENST00000696039.1:n.894+1G>T
ENST00000696058.1:c.606+1G>T
ENST00000696059.1:c.*551+1G>T
ENST00000696060.1:c.606+1G>T
ENST00000696061.1:c.603+1G>T
ENST00000696062.1:c.669+1G>T
ENST00000696063.1:c.681+1G>T
ENST00000696064.1:c.453+1G>T
ENST00000696065.1:c.66-1271G>T
ENST00000696074.1:n.222+1G>T
ENST00000696075.1:c.*576+1G>T
ENST00000696076.1:c.606+1G>T
ENST00000696077.1:c.603+1G>T
ENST00000696078.1:c.606+1G>T
ENST00000696079.1:c.606+1G>T
ENST00000696080.1:c.606+1G>T
ENST00000696081.1:n.725+1G>T
ENST00000696082.1:c.684+1G>T
ENST00000696083.1:n.1487+1G>T
ENST00000696084.1:n.707+1G>T
ENST00000696104.1:c.363-1271G>T
ENST00000696105.1:c.*147+1G>T
ENST00000372874.9:c.606+1G>T
ENST00000372874.8:c.606+1G>T
ENST00000372887.5:c.*225C>A
ENST00000464097.5:n.280+1G>T
ENST00000492931.5:n.690+1G>T
ENST00000536532.5:c.606+1G>T
ENST00000537820.1:c.606+1G>T
ENST00000539235.5:c.219-1123G>T
NM_000022.2:c.606+1G>T
NM_000022.3:c.606+1G>T
NM_001322050.1:c.201+1G>T
NM_001322051.1:c.606+1G>T
NR_136160.1:n.757+1G>T
NM_001322050.2:c.201+1G>T
NM_001322051.2:c.606+1G>T
NR_136160.2:n.698+1G>T

Likely Pathogenic

Met criteria codes 2
PM2_Supporting PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Severe Combined Immunodeficiency Disease VCEP
The c.606+1G>T (NM_000022.4) variant in ADA occurs within the canonical donor splice site (+1) of intron 6. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 6, resulting in a frameshift (p.(Asn160Argfs*48) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4 is 0.00002994 (1/33402 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting). There are no publications for this variant in the literature. As per the SCID VCEP specifications and the Bayesian interpretation of the ACMG/AMP combining rules, 1 very strong and 1 supporting criteria results in a Likely Pathogenic classification. In summary, this variant meets the criteria to be classified as a Likely 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,PVS1 (VCEP specifications version 1).
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4 is 0.00002994 (1/33402 alleles) in African/African American population, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, meeting this criterion (PM2_Supporting).
PVS1
The c.606+1G>T (NM_000022.4) variant in ADA occurs within the canonical donor splice site (+1) of intron 6. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 6, resulting in a frameshift (p.(Asn160Argfs*48) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).
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