chr5-35873604-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002185.5(IL7R):c.662G>T(p.Ser221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
IL7R
NM_002185.5 missense
NM_002185.5 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 5.76
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 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
?
Variant 5-35873604-G-T is Pathogenic according to our data. Variant chr5-35873604-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 134528.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.662G>T | p.Ser221Ile | missense_variant | 5/8 | ENST00000303115.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IL7R | ENST00000303115.8 | c.662G>T | p.Ser221Ile | missense_variant | 5/8 | 1 | NM_002185.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461644Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727138
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Immunodeficiency 104 Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Nov 14, 2023 | The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported. PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant. This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met. The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 221 of the IL7R protein (p.Ser221Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 17201233, 18641513; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 134528). 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. - |
Severe combined immunodeficiency disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: IL7R c.662G>T (p.Ser221Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes. c.662G>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency (example, Lebet_2008, Ponda_2006). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17201233, 18641513). Two 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 | Nov 11, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(S201I); This variant is associated with the following publications: (PMID: 8617735, 15661025, 19141282, 18641513, 31817502, 17201233) - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of catalytic residue at S221 (P = 0.0674);Gain of catalytic residue at S221 (P = 0.0674);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at