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]

Variant: NM_000022.4(ADA):c.975+1G>A

CA409118697

984454 (ClinVar)

Gene: ADA (HGNC:100)
Condition: adenosine deaminase deficiency (MONDO:0007064)
Inheritance Mode: Autosomal recessive inheritance
UUID: 0136b3ad-65d9-44c7-ae99-4d4d38a96521
Approved on: 2024-02-21
Published on: 2024-02-21

HGVS expressions

NM_000022.4(ADA):c.975+1G>A
NM_000022.4:c.975+1G>A
NC_000020.11:g.44621017C>T
CM000682.2:g.44621017C>T
NC_000020.10:g.43249658C>T
CM000682.1:g.43249658C>T
NC_000020.9:g.42683072C>T
NG_007385.1:g.35719G>A
ENST00000492931.6:n.1142+1G>A
ENST00000536076.2:c.822+1G>A
ENST00000536532.6:c.*118+1G>A
ENST00000537820.2:c.903+1G>A
ENST00000539235.6:c.*359+1G>A
ENST00000695889.1:c.450+1G>A
ENST00000695890.1:n.4471G>A
ENST00000695891.1:c.515+1G>A
ENST00000695927.1:c.1053+1G>A
ENST00000695949.1:c.900+1G>A
ENST00000695956.1:c.130+1G>A
ENST00000695957.1:c.*466+1G>A
ENST00000695991.1:c.513+1G>A
ENST00000695992.1:c.*118+1G>A
ENST00000695993.1:c.975+1G>A
ENST00000695994.1:c.*118+1G>A
ENST00000695995.1:c.585+1G>A
ENST00000695996.1:n.1057+1G>A
ENST00000696003.1:n.2759+1G>A
ENST00000696004.1:n.1144G>A
ENST00000696005.1:c.425+1G>A
ENST00000696006.1:c.*118+1G>A
ENST00000696007.1:c.902+1G>A
ENST00000696008.1:n.3329+1G>A
ENST00000696017.1:c.972+1G>A
ENST00000696034.1:c.*118+1G>A
ENST00000696035.1:n.1161+1G>A
ENST00000696036.1:n.1676+1G>A
ENST00000696037.1:n.2652+1G>A
ENST00000696038.1:c.*732+1G>A
ENST00000696039.1:n.1339+1G>A
ENST00000696058.1:c.972+1G>A
ENST00000696059.1:c.*920+1G>A
ENST00000696060.1:c.1044+1G>A
ENST00000696061.1:c.972+1G>A
ENST00000696062.1:c.1038+1G>A
ENST00000696063.1:c.1050+1G>A
ENST00000696064.1:c.822+1G>A
ENST00000696065.1:c.297+1G>A
ENST00000696072.1:n.330+1G>A
ENST00000696073.1:n.1286+1G>A
ENST00000696074.1:n.526+1G>A
ENST00000696075.1:c.*945+1G>A
ENST00000696076.1:c.1044+1G>A
ENST00000696077.1:c.969+1G>A
ENST00000696078.1:c.972+1G>A
ENST00000696079.1:c.972+1G>A
ENST00000696080.1:c.975+1G>A
ENST00000696081.1:n.1094+1G>A
ENST00000696082.1:c.1050+1G>A
ENST00000696083.1:n.1932+1G>A
ENST00000696084.1:n.1152+1G>A
ENST00000696104.1:c.*44+1G>A
ENST00000372874.9:c.975+1G>A
ENST00000372874.8:c.975+1G>A
ENST00000372887.5:c.152-2916C>T
ENST00000464097.5:n.726G>A
ENST00000492931.5:n.1135+1G>A
ENST00000536532.5:c.*118+1G>A
ENST00000537820.1:c.903+1G>A
ENST00000539235.5:c.*359+1G>A
NM_000022.2:c.975+1G>A
NM_000022.3:c.975+1G>A
NM_001322050.1:c.570+1G>A
NM_001322051.1:c.903+1G>A
NR_136160.1:n.1061+1G>A
NM_001322050.2:c.570+1G>A
NM_001322051.2:c.903+1G>A
NR_136160.2:n.1002+1G>A
More

Pathogenic

Met criteria codes 3
PP4_Moderate 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.975+1G>A (NM_000022.4) variant in ADA occurs within the canonical splice site donor of intron 10. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 2/1111992 alleles) of the c.975+1G>A variant in ADA is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. At least one patient with this variant displayed * Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), which is highly specific for ADA SCID (PP4_Moderate, PMID: 8227344). In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PVS1, PM2_Supporting, and PP4_Moderate.
Met criteria codes
PP4_Moderate
At least one patient with this variant displayed * Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (2pts), which is highly specific for ADA SCID (PP4_Moderate, PMID: 8227344).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 2/1111992 alleles) of the c.975+1G>A variant in ADA is 0.0000003 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.
PVS1
The c.975+1G>A (NM_000022.4) variant in ADA occurs within the canonical splice site donor of intron 10. It is expected to disrupt RNA splicing, disrupting the reading frame, and is predicted to undergo NMD. (PVS1).
Curation History
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