rs193922641
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_002185.5(IL7R):c.353G>A(p.Cys118Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
IL7R
NM_002185.5 missense
NM_002185.5 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 1.57
Genes affected
IL7R (HGNC:6024): (interleukin 7 receptor) The protein encoded by this gene is a receptor for interleukin 7 (IL7). The function of this receptor requires the interleukin 2 receptor, gamma chain (IL2RG), which is a common gamma chain shared by the receptors of various cytokines, including interleukins 2, 4, 7, 9, and 15. This protein has been shown to play a critical role in V(D)J recombination during lymphocyte development. Defects in this gene may be associated with severe combined immunodeficiency (SCID). Alternatively spliced transcript variants have been found. [provided by RefSeq, Dec 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-35867437-G-A is Pathogenic according to our data. Variant chr5-35867437-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 36392.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IL7R | NM_002185.5 | c.353G>A | p.Cys118Tyr | missense_variant | 3/8 | ENST00000303115.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IL7R | ENST00000303115.8 | c.353G>A | p.Cys118Tyr | missense_variant | 3/8 | 1 | NM_002185.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151962Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250510Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135422
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Immunodeficiency 104 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 01, 2021 | ACMG classification criteria: PS4 strong, PM2 moderate, PM3 strong, PP4 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 118 of the IL7R protein (p.Cys118Tyr). This variant is present in population databases (rs193922641, gnomAD 0.006%). This missense change has been observed in individuals with severe combined immunodeficiency (PMID: 15661025, 16492442, 17827065, 24759676, 27833609). It has also been observed to segregate with disease in related individuals. This variant is also known as 375G>A (p.C118Y). ClinVar contains an entry for this variant (Variation ID: 36392). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL7R protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Oct 10, 2023 | The missense variant NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr) occurs at a low filtering allele frequency of 0.000009610 in gnomAD v2.1.1 (<0.00004129; PM2_Supporting). At least 14 SCID or Omenn syndrome patients have been reported with this variant in 10 publications (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025, 34153518, 17827065, 24578017, 27833609). Several have highly specific phenotypes which meet criteria for PP4 (PMIDs: 35503492, 24759676) and one patient (PMID: 27833609) had sufficient information to meet PP4_moderate; this patient fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID), with at T-B+NK+ subtype, absence of CD127 expression, and reduced f IL-7 induced pSTAT5 (Y694) in T-cells, which together are highly specific for IL7R-related SCID (PP4_moderate). Additionally, the variant has been reported to segregate with SCID in 2 affected family members from family 2 in PMID: 15661025 (PP1). Of the 14 patients, eight patients have been reported homozygous for this variant (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025; PM3) and six compound heterozygous; second variants were reported in P19 (PMID: 35503492) and the SCID patient reported in Zago CA et al. (PMID: 24759676) both harboring c.361dup without confirmation of trans phase (classified Pathogenic by the SCID VCEP; 0.5+0.5pt), the patients reported by Tsilifis C et al. (PMID: 34153518) and Butte MJ et al. (PMID: 17827065) both harbor c.379+288G>A confirmed in trans (provisionally classified by the SCID VCEP as VUS; 0.25+0.25pt), Case 1 (PMID: 24578017) has c.83-2A>T without confirmation of trans phase (provisionally classified as Pathogenic by the SCID VCEP; 0.5pt), and the patient reported by Gallego-Bustos F et al. (PMID: 27833609) has c.333T>A confirmed in trans (provisionally classified Likely Pathogenic by the SCID VCEP; 1pt), Total=4pts (PM3_VeryStrong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_supporting, PM3_VeryStrong, PP1, PP4_moderate. (SCID VCEP specifications version 1.0). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.353G>A;p.(Cys118Tyr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 36392; PMID: 15661025; 16492442; 17827065; 18403192; 24759676; 27833609) - PS4. The variant is present at low allele frequencies population databases (rs193922641– gnomAD 0.0003948%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Cys118Tyr) was detected in trans with a Pathogenic variant (PMID: 24759676) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2023 | Variant summary: IL7R c.353G>A (p.Cys118Tyr) results in a non-conservative amino acid change located in the IL-7Ralpha, fibronectin type III domain (IPR040997) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250650 control chromosomes (gnomAD and publication data). c.353G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (e.g. Giliani_2005, Giliani_2006, Butte_2007, Zago_2014, Gallego-Bustos_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17827065, 27833609, 15661025, 16492442, 24759676). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C98Y); This variant is associated with the following publications: (PMID: 16492442, 17827065, 24759676, 31589614, 35503492, 34573280, 34598035, 15661025, 35601409, 19141282, 24578017, 27833609) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;D
Polyphen
B;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at