rs9292618

Variant names:

• chr5-35878410-G-A
• rs9292618
• NM_002185.5:c.*1924G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002185.5(IL7R):​c.*1924G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 232,966 control chromosomes in the GnomAD database, including 2,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1318 hom., cov: 33)
  • Exomes 𝑓: 0.13 (748 hom.)
• Consequence: IL7R NM_002185.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 104

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-35878410-G-A is Benign according to our data. Variant chr5-35878410-G-A is described in ClinVar as Benign. ClinVar VariationId is 353301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002185.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	NM_002185.5	MANE Select	c.*1924G>A		3_prime_UTR	Exon 8 of 8	NP_002176.2
	IL7R	NR_120485.3		n.3128G>A		non_coding_transcript_exon	Exon 6 of 6
	IL7R	NM_001437964.1		c.*2802G>A		3_prime_UTR	Exon 7 of 7	NP_001424893.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	ENST00000303115.8	TSL:1 MANE Select	c.*1924G>A		3_prime_UTR	Exon 8 of 8	ENSP00000306157.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19948 AN: 152060 Hom.: 1318 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0636

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.134 AC: 10808 AN: 80788 Hom.: 748 Cov.: 0 AF XY: 0.134 AC XY: 4968 AN XY: 37124

African (AFR) AF: 0.133 AC: 516 AN: 3892

American (AMR) AF: 0.157 AC: 392 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 593 AN: 5110

East Asian (EAS) AF: 0.112 AC: 1274 AN: 11366

South Asian (SAS) AF: 0.0500 AC: 35 AN: 700

European-Finnish (FIN) AF: 0.138 AC: 8 AN: 58

Middle Eastern (MID) AF: 0.112 AC: 55 AN: 490

European-Non Finnish (NFE) AF: 0.139 AC: 6963 AN: 49916

Other (OTH) AF: 0.144 AC: 972 AN: 6758

GnomAD4 genome AF: 0.131 AC: 19940 AN: 152178 Hom.: 1318 Cov.: 33 AF XY: 0.128 AC XY: 9513 AN XY: 74394

African (AFR) AF: 0.131 AC: 5444 AN: 41506

American (AMR) AF: 0.143 AC: 2188 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3470

East Asian (EAS) AF: 0.144 AC: 746 AN: 5182

South Asian (SAS) AF: 0.0628 AC: 303 AN: 4826

European-Finnish (FIN) AF: 0.100 AC: 1064 AN: 10600

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.136 AC: 9265 AN: 67996

Other (OTH) AF: 0.144 AC: 304 AN: 2112

Alfa AF: 0.134 Hom.: 219

Bravo AF: 0.139

Asia WGS AF: 0.108 AC: 374 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Immunodeficiency 104 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.075
DANN	Benign	0.41
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs9292618; hg19: chr5-35878512;