5-35874473-C-T

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.731C>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 244 (p.Thr244Ile).The filtering allele frequency (the lower threshold of the 95% CI of 21695/63972 alleles) of the c.731C>T variant in IL7R is 0.2678 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 53760 homozygous adults are reported in gnomAD v.4. BS2_Supporting is Met. 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/CA160105/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.21 ( 3852 hom., cov: 32)

Exomes 𝑓: 0.26 ( 49908 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:2

Conservation

PhyloP100: -0.430

Publications

369 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.731C>T	p.Thr244Ile	missense_variant	Exon 6 of 8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 link	c.731C>T	p.Thr244Ile	missense_variant	Exon 6 of 8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31935

AN:

151958

Hom.:

3853

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.310

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.188

GnomAD2 exomes

AF:

0.232

AC:

58330

AN:

251338

AF XY:

0.236

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.180

Gnomad ASJ exome

AF:

0.220

Gnomad EAS exome

AF:

0.170

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.249

GnomAD4 exome

AF:

0.256

AC:

373494

AN:

1456326

Hom.:

49908

Cov.:

AF XY:

0.256

AC XY:

185396

AN XY:

724944

show subpopulations

African (AFR)

AF:

0.0993

AC:

3319

AN:

33408

American (AMR)

AF:

0.183

AC:

8165

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5948

AN:

26112

East Asian (EAS)

AF:

0.180

AC:

7152

AN:

39662

South Asian (SAS)

AF:

0.208

AC:

17959

AN:

86168

European-Finnish (FIN)

AF:

0.338

AC:

18048

AN:

53410

Middle Eastern (MID)

AF:

0.154

AC:

887

AN:

5758

European-Non Finnish (NFE)

AF:

0.269

AC:

297360

AN:

1106866

Other (OTH)

AF:

0.243

AC:

14656

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

13344

26687

40031

53374

66718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9864

19728

29592

39456

49320

<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:

0.210

AC:

31942

AN:

152076

Hom.:

3852

Cov.:

AF XY:

0.212

AC XY:

15763

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.101

AC:

4209

AN:

41482

American (AMR)

AF:

0.176

AC:

2691

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

804

AN:

3466

East Asian (EAS)

AF:

0.166

AC:

860

AN:

5166

South Asian (SAS)

AF:

0.201

AC:

969

AN:

4820

European-Finnish (FIN)

AF:

0.345

AC:

3647

AN:

10562

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18038

AN:

67980

Other (OTH)

AF:

0.189

AC:

399

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1273

2545

3818

5090

6363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.243

Hom.:

21819

Bravo

AF:

0.194

TwinsUK

AF:

0.273

AC:

1011

ALSPAC

AF:

0.277

AC:

1067

ESP6500AA

AF:

0.110

AC:

484

ESP6500EA

AF:

0.267

AC:

2300

ExAC

AF:

0.233

AC:

28253

Asia WGS

AF:

0.207

AC:

718

AN:

3478

EpiCase

AF:

0.248

EpiControl

AF:

0.254

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Benign:5

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.731C>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 244 (p.Thr244Ile). The filtering allele frequency (the lower threshold of the 95% CI of 21695/63972 alleles) of the c.731C>T variant in IL7R is 0.2678 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 53760 homozygous adults are reported in gnomAD v.4. BS2_Supporting is Met. 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). -

Aug 25, 2021

Fulgent Genetics, Fulgent Genetics

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3Other: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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -

not provided

Benign:2Other:1

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

- -

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: 28964592, 21833088, 27188999, 17660817, 18721276, 24728327, 21670443, 17660530, 17660816, 21629267, 19523791, 19626041) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.77

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.46

PhyloP100

-0.43

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.15

REVEL

Benign

0.22

Sift

Benign

0.52

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.027

MPC

0.015

ClinPred

0.00022

GERP RS

-2.5

Varity_R

0.033

gMVP

0.22

Mutation Taster

=98/2

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