rs3194051

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1066A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 356 (p.Ile356Val).The filtering allele frequency (the lower threshold of the 95% CI of 25619/74900 alleles) of the c.1066A>G variant in IL7R is 0.3385 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 55069 adult homozygous occurrences are described in gnomAD (BS2_Supporting).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA160114/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.28 ( 6159 hom., cov: 31)

Exomes 𝑓: 0.25 ( 48910 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:2

Conservation

PhyloP100: 1.06

Publications

117 publications found

Variant links:

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

IL7R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL7R	NM_002185.5 link	c.1066A>G	p.Ile356Val	missense_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 link	c.1066A>G	p.Ile356Val	missense_variant	Exon 8 of 8	1	NM_002185.5	ENSP00000306157.3

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42072

AN:

151874

Hom.:

6159

Cov.:

show subpopulations

Gnomad AFR

AF:

0.342

Gnomad AMI

AF:

0.340

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.0724

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.275

GnomAD2 exomes

AF:

0.239

AC:

59865

AN:

250888

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.0673

Gnomad FIN exome

AF:

0.296

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.254

AC:

371947

AN:

1461740

Hom.:

48910

Cov.:

AF XY:

0.254

AC XY:

184696

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.342

AC:

11458

AN:

33480

American (AMR)

AF:

0.158

AC:

7083

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

7107

AN:

26130

East Asian (EAS)

AF:

0.0707

AC:

2805

AN:

39690

South Asian (SAS)

AF:

0.207

AC:

17897

AN:

86254

European-Finnish (FIN)

AF:

0.293

AC:

15671

AN:

53410

Middle Eastern (MID)

AF:

0.292

AC:

1686

AN:

5768

European-Non Finnish (NFE)

AF:

0.264

AC:

293421

AN:

1111904

Other (OTH)

AF:

0.245

AC:

14819

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

18012

36024

54035

72047

90059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9680

19360

29040

38720

48400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.277

AC:

42076

AN:

151992

Hom.:

6159

Cov.:

AF XY:

0.275

AC XY:

20410

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.342

AC:

14161

AN:

41420

American (AMR)

AF:

0.221

AC:

3378

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

915

AN:

3462

East Asian (EAS)

AF:

0.0728

AC:

376

AN:

5164

South Asian (SAS)

AF:

0.197

AC:

946

AN:

4804

European-Finnish (FIN)

AF:

0.288

AC:

3049

AN:

10580

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18277

AN:

67958

Other (OTH)

AF:

0.271

AC:

572

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1512

3023

4535

6046

7558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.268

Hom.:

26378

Bravo

AF:

0.274

TwinsUK

AF:

0.268

AC:

992

ALSPAC

AF:

0.250

AC:

964

ESP6500AA

AF:

0.350

AC:

1542

ESP6500EA

AF:

0.264

AC:

2271

ExAC

AF:

0.244

AC:

29666

Asia WGS

AF:

0.150

AC:

523

AN:

3478

EpiCase

AF:

0.277

EpiControl

AF:

0.282

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 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. -

Apr 03, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.1066A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Isoleucine by Valine at amino acid 356 (p.Ile356Val). The filtering allele frequency (the lower threshold of the 95% CI of 25619/74900 alleles) of the c.1066A>G variant in IL7R is 0.3385 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 55069 adult homozygous occurrences are described in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) -

not specified

Benign:2Other:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 40. Only high quality variants are reported. -

not provided

Benign:2Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21297633, 15674389, 24728327, 23818875, 17660816) -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.37

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.13

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

1.1

PrimateAI

Benign

0.27

PROVEAN

Benign

0.080

REVEL

Benign

0.019

Sift

Benign

0.68

Sift4G

Benign

1.0

Polyphen

0.044

Vest4

0.0060

MPC

0.014

ClinPred

0.0074

GERP RS

3.2

Varity_R

0.031

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over