5-35873646-C-G

Position:

• chr5-35873646-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.704C>G (p.Ser235Ter)(NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has not been identified in the literature to our knowledge. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA359431210/MONDO:0012163/119

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL7R NM_002185.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.002941
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -0.510

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]

IL7R (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL7R	NM_002185.5	c.704C>G	p.Ser235*	stop_gained, splice_region_variant	5/8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8	c.704C>G	p.Ser235*	stop_gained, splice_region_variant	5/8	1	NM_002185.5	ENSP00000306157.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Immunodeficiency 104 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Dec 29, 2017	This stop-gain variant is predicted to result in premature termination of the IL7R protein. This variant has not been previously reported in the literature to our knowledge, but other pathogenic stop-gain changes have been reported in the literature in association with severe combined immunodeficiency (PMID: 15615257, 27807805). This variant is absent from population databases, thus is presumed to be rare. Based on the overall evidence, we classified the c.704C>G (p.Ser235Ter) variant as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2018	This sequence change creates a premature translational stop signal (p.Ser235*) in the IL7R gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IL7R-related disease. Loss-of-function variants in IL7R are known to be pathogenic (PMID: 21664875, 26123418). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.704C>G (p.Ser235Ter)(NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has not been identified in the literature to our knowledge. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1, PM2_Supporting. (VCEP specifications version 1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.23	N
Vest4		0.56
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs766555082; hg19: chr5-35873748;