Variant: NM_000022.4(ADA):c.591T>A (p.His197Gln)

CA9871621

338509 (ClinVar)

Gene: ADA

Condition: adenosine deaminase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: b9b9943b-04ab-4f41-b5f1-62b4b72d6d1c

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000022.4:c.591T>A
NM_000022.4(ADA):c.591T>A (p.His197Gln)
NC_000020.11:g.44624217A>T
CM000682.2:g.44624217A>T
NC_000020.10:g.43252858A>T
CM000682.1:g.43252858A>T
NC_000020.9:g.42686272A>T
NG_007385.1:g.32519T>A
ENST00000372874.9:c.591T>A
ENST00000372874.8:c.591T>A
ENST00000372887.5:c.*241A>T
ENST00000464097.5:n.265T>A
ENST00000492931.5:n.675T>A
ENST00000536532.5:c.591T>A
ENST00000537820.1:c.591T>A
ENST00000539235.5:c.219-1139T>A
NM_000022.2:c.591T>A
NM_000022.3:c.591T>A
NM_001322050.1:c.186T>A
NM_001322051.1:c.591T>A
NR_136160.1:n.742T>A
NM_001322050.2:c.186T>A
NM_001322051.2:c.591T>A
NR_136160.2:n.683T>A

Likely Benign

• Met criteria codes: BS1

• Not Met criteria codes: BS2 PM2 BA1 PP3

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

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000022.4:c.591T>A variant in ADA is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 197 (p.His197Gln). This variant has a MAF of 0.005546 (57/10278 alleles) in the Ashkenazi Jewish population in gnomAD, which is greater than the frequency specified for BS1 by the SCID VCEP for ADA (>0.00161). As per SCID VCEP specifications for ADA, we are allowed to count bottleneck populations for BS1. Therefore, BS1 is met. There are no homozygotes in gnoMAD. This variant has not been reported in the literature in individuals with severe combined immunodeficiency (SCID), and no functional experimental data has been published for this variant. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG criteria applied: BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

Met criteria codes

• BS1: This variant has a MAF of 0.005546 (57/10278 alleles) in the Ashkenazi Jewish population in gnomAD, which is greater than the frequency specified for BS1 by the SCID VCEP for ADA (>0.00161). As per SCID VCEP specifications for ADA, we are allowed to count bottleneck populations for BS1, therefore BS1 is met. There are no homozygotes in gnoMAD.

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: This variant has a MAF of 0.005546 (57/10278 alleles) in the Ashkenazi Jewish population in gnomAD, which does not exceed the frequency specified for BA1 by the SCID VCEP for ADA (>0.00721). Therefore BA1 is NOT met.
• PP3: several in silico predictors support a deleterious effect, however as per SCID VCEP specification for ADA, these predictions do NOT apply to missense variants. Therefore PP3 is not met. Of note: this variant is included in PMID: 31781678 (see supplemental table 1), but all the data is from computational algorithms (SIFT, PolyPhen, etc) so this data still does not apply (there is no in vitro or in vivo functional data reported in this paper, only computational data). PP3 does not apply.