rs10491434

Variant names:

• chr5-35877812-A-G
• rs10491434
• NM_002185.5:c.*1326A>G

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.*1326A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 232,966 control chromosomes in the GnomAD database, including 10,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8129 hom., cov: 32)
  • Exomes 𝑓: 0.25 (2757 hom.)
• Consequence: IL7R NM_002185.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00
• Publications: 19 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=-0.85).
• BP6: Variant 5-35877812-A-G is Benign according to our data. Variant chr5-35877812-A-G is described in ClinVar as Benign. ClinVar VariationId is 353290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5	c.*1326A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8	c.*1326A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_002185.5	ENSP00000306157.3

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47107 AN: 151884 Hom.: 8126 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.248 AC: 20065 AN: 80964 Hom.: 2757 Cov.: 0 AF XY: 0.247 AC XY: 9208 AN XY: 37210

African (AFR) AF: 0.453 AC: 1763 AN: 3892

American (AMR) AF: 0.210 AC: 525 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 1415 AN: 5122

East Asian (EAS) AF: 0.0757 AC: 864 AN: 11410

South Asian (SAS) AF: 0.199 AC: 140 AN: 702

European-Finnish (FIN) AF: 0.310 AC: 18 AN: 58

Middle Eastern (MID) AF: 0.315 AC: 155 AN: 492

European-Non Finnish (NFE) AF: 0.268 AC: 13397 AN: 50022

Other (OTH) AF: 0.264 AC: 1788 AN: 6766

GnomAD4 genome AF: 0.310 AC: 47131 AN: 152002 Hom.: 8129 Cov.: 32 AF XY: 0.307 AC XY: 22822 AN XY: 74292

African (AFR) AF: 0.456 AC: 18899 AN: 41404

American (AMR) AF: 0.234 AC: 3567 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 918 AN: 3466

East Asian (EAS) AF: 0.0750 AC: 388 AN: 5174

South Asian (SAS) AF: 0.199 AC: 959 AN: 4828

European-Finnish (FIN) AF: 0.289 AC: 3057 AN: 10568

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.269 AC: 18302 AN: 67980

Other (OTH) AF: 0.303 AC: 640 AN: 2112

Alfa AF: 0.278 Hom.: 4010

Bravo AF: 0.312

Asia WGS AF: 0.163 AC: 567 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 12, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.3
DANN	Benign	0.72
PhyloP100		-1.0
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: rs10491434; hg19: chr5-35877914;