Evidence Repository - Clinical Genome Resources

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.1078+2T>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409118270

558340 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7d64c528-32ad-468c-ab91-3f9f1a747ae9

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_000022.4:c.1078+2T>A

NM_000022.4(ADA):c.1078+2T>A

NC_000020.11:g.44620297A>T

CM000682.2:g.44620297A>T

NC_000020.10:g.43248938A>T

CM000682.1:g.43248938A>T

NC_000020.9:g.42682352A>T

NG_007385.1:g.36439T>A

ENST00000372874.9:c.1078+2T>A

ENST00000372874.8:c.1078+2T>A

ENST00000372887.5:c.152-3636A>T

ENST00000464097.5:n.1444+2T>A

ENST00000492931.5:n.1238+2T>A

ENST00000536532.5:c.*221+2T>A

ENST00000537820.1:c.1006+2T>A

ENST00000539235.5:c.*462+2T>A

NM_000022.2:c.1078+2T>A

NM_000022.3:c.1078+2T>A

NM_001322050.1:c.673+2T>A

NM_001322051.1:c.1006+2T>A

NR_136160.1:n.1164+2T>A

NM_001322050.2:c.673+2T>A

NM_001322051.2:c.1006+2T>A

NR_136160.2:n.1105+2T>A

Likely Pathogenic

PVS1_Moderate PM3 PM2_Supporting PP4_Moderate

BS2

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

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.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.

PVS1_Moderate

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.

PM3

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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

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.

BS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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