Variant: NM_002185.5(IL7R):c.538-1G>A

CA359430531

14841 (ClinVar)

Gene: IL7R

Condition: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive

Inheritance Mode: Autosomal recessive inheritance

UUID: 9631cf2d-22e9-44f7-84dc-041605844b59

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_002185.5:c.538-1G>A
NM_002185.5(IL7R):c.538-1G>A
NC_000005.10:g.35873479G>A
CM000667.2:g.35873479G>A
NC_000005.9:g.35873581G>A
CM000667.1:g.35873581G>A
NC_000005.8:g.35909338G>A
NG_009567.1:g.21591G>A
ENST00000303115.8:c.538-1G>A
ENST00000303115.7:c.538-1G>A
ENST00000506850.5:c.538-1G>A
ENST00000509668.1:n.279G>A
ENST00000514217.5:c.538-2033G>A
NM_002185.3:c.538-1G>A
NR_120485.1:n.641-2033G>A
NM_002185.4:c.538-1G>A
NR_120485.2:n.667-2033G>A
NR_120485.3:n.625-2033G>A

Pathogenic

• Met criteria codes: PVS1 PM2_Supporting PM3 PP4

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 IL7R Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.538-1G>A (NM_002185.5) variant in IL7R occurs within the canonical splice acceptor site (-1) of intron 4. It is predicted to cause either skipping of biologically relevant exon 5 or use of cryptic splicing site 25 nt upstream (predicted by varSEAK) or 17 nt downstream (predicted by SpliceAI) of the canonical site. In all cases, the variant is predicted to result in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. PVS1 is met. The Popmax filtering allele frequency (the upper threshold of the 95% CI of 2/112934) of the c.538-1G>A variant in IL7R is 0.000002940 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Additionally, no homozygous individuals have been reported. At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + Reduced CD127 expression (1pt) + T-B+NK+ lymphocyte subset profile (0.25pt), which is highly specific for SCID. (Total of 1.75 points, PP4 is met, PMID 9843216). The same patient was compound heterozygous for the variant and p.Trp217Ter, likely pathogenic according to SCID VCEP specifications. The phase of those was confirmed in trans by cloning assay (1pt in total, PM3 is met). In summary, this variant is classified as 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, PM3, PP4.

Met criteria codes

• PVS1: The c.538-1G>A (NM_002185.5) variant in IL7R occurs within the canonical splice acceptor site (-1) of intron 4. It is predicted to cause either skipping of biologically relevant exon 5 or use of cryptic splicing site 25 nt upstream (predicted by varSEAK) or 17 nt downstream (predicted by SpliceAI) of the canonical site. In all cases, the variant is predicted to result in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. PVS1 is met.
• PM2_Supporting: The Popmax filtering allele frequency (the upper threshold of the 95% CI of 2/112934) of the c.538-1G>A variant in IL7R is 0.000002940 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Additionally, no homozygous individuals have been reported.
• PM3: This variant has been detected in one individual with SCID. The patient was compound heterozygous for the variant and p.Trp217Ter, likely pathogenic according to SCID VCEP specifications. The phase of those was confirmed in trans by cloning assay (1pt in total, PM3 is met).
• PP4: At least one patient with this variant displayed: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5pt) + Reduced CD127 expression (1pt) + T-B+NK+ lymphocyte subset profile (0.25pt), which is highly specific for SCID. (Total of 1.75 points, PP4 is met, PMID 9843216).