rs937746465
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_002185.5(IL7R):c.83-2A>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000031 in 1,613,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
IL7R
NM_002185.5 splice_acceptor
NM_002185.5 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.46
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.9, offset of -22, new splice context is: tttatttgtttcattaacAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 5-35860850-A-T is Pathogenic according to our data. Variant chr5-35860850-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 353259.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.83-2A>T | splice_acceptor_variant | ENST00000303115.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IL7R | ENST00000303115.8 | c.83-2A>T | splice_acceptor_variant | 1 | NM_002185.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251156Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135738
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461108Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726888
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Immunodeficiency 104 Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 03, 2016 | The IL7R c.83-2A>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.83-2A>T variant has been reported in two individuals with severe combined immune deficiency, including one who carried the variant in a compound heterozygous state with a missense variant and one who carried the variant in a heterozygous state with no second variant identified (Giliani et al. 2005; Vogel et al. 2014). The variant is reported at a frequency of 0.000058 in the Latino population of the Genome Aggregation Database. This frequency is based on two alleles in a region of good sequency coverage, so the variant is presumed to be rare. Based on the evidence from the literature and due to the potential impact of splice acceptor variants, the c.83-2A>T variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe combined immune deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen | Oct 10, 2023 | The NM_002185.5(IL7R):c.83-2A>T variant occurs within the canonical splice acceptor site of intron 1. It is predicted to cause skipping of biologically relevant exon 2, resulting in a frameshift with a premature stop codon in exon 3/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Patient P4, of PMID: 15661025, is homozygous for this variant (PM3_supporting). At least four probands have been reported in the literature with this variant; however, insufficient information was available to apply PP4 (PMIDs: 32888943, 24578017, 21664875, 15661025). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005649 (2/35406 alleles) in the Latino/Admixed American population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129; PM2_Supporting). 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: PVS1, PM2_supporting, PM3_supporting. (SCID VCEP specifications version 1.0). - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with IL7R related disorder (ClinVar ID: VCV000353259). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change affects an acceptor splice site in intron 1 of the IL7R gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IL7R are known to be pathogenic (PMID: 21664875, 26123418). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with severe combined immunodeficiency (PMID: 15661025, 24578017). This variant is also known as exon 2 -2int1 A>T. ClinVar contains an entry for this variant (Variation ID: 353259). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2015 | The c.83-2A>T splice site variant in the IL7R gene has been previously reported, as -2int1 using alternative nomenclature, in association with SCID (Giliani et al., 2005). This variant destroys the canonical splice acceptor site in intron 1, and is expected to cause abnormal gene splicing. Therefore, we consider c.83-2A>T to be a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -20
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at