chr5-35871171-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP7BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.495C>T (p.His165=) variant (NM_002185.5) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 5398/35384) of the c.495C>T variant in IL7R is 0.1491 for Latino/Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 2363 homozygous individuals were reported (BS2_Supporting is met).In summary, this variant is classified as Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BP7, BA1, and BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291241/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.13 ( 1327 hom., cov: 33)

Exomes 𝑓: 0.13 ( 13845 hom. )

Consequence

IL7R
NM_002185.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: -0.446

Publications

31 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 -10 ACMG points.

BP7

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

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.495C>T	p.His165His	synonymous_variant	Exon 4 of 8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IL7R	ENST00000303115.8 link	c.495C>T	p.His165His	synonymous_variant	Exon 4 of 8	1	NM_002185.5	ENSP00000306157.3	P16871-1
IL7R	ENST00000506850.5 link	c.495C>T	p.His165His	synonymous_variant	Exon 4 of 6	2		ENSP00000421207.1	P16871-3
IL7R	ENST00000514217.5 link	n.495C>T		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000427688.1	B8YG18

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

19986

AN:

151976

Hom.:

1327

Cov.:

show subpopulations

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:

0.0632

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.146

GnomAD2 exomes

AF:

0.127

AC:

31804

AN:

251042

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.152

Gnomad FIN exome

AF:

0.0991

Gnomad NFE exome

AF:

0.138

Gnomad OTH exome

AF:

0.132

GnomAD4 exome

AF:

0.134

AC:

195901

AN:

1457346

Hom.:

13845

Cov.:

AF XY:

0.132

AC XY:

95373

AN XY:

725238

show subpopulations

African (AFR)

AF:

0.128

AC:

4264

AN:

33390

American (AMR)

AF:

0.154

AC:

6886

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3117

AN:

26104

East Asian (EAS)

AF:

0.133

AC:

5283

AN:

39648

South Asian (SAS)

AF:

0.0614

AC:

5293

AN:

86212

European-Finnish (FIN)

AF:

0.100

AC:

5364

AN:

53396

Middle Eastern (MID)

AF:

0.140

AC:

806

AN:

5748

European-Non Finnish (NFE)

AF:

0.141

AC:

156724

AN:

1107898

Other (OTH)

AF:

0.136

AC:

8164

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

7361

14722

22082

29443

36804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5686

11372

17058

22744

28430

<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:

0.131

AC:

19978

AN:

152094

Hom.:

1327

Cov.:

AF XY:

0.128

AC XY:

9523

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.132

AC:

5464

AN:

41464

American (AMR)

AF:

0.143

AC:

2188

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

455

AN:

3472

East Asian (EAS)

AF:

0.145

AC:

747

AN:

5168

South Asian (SAS)

AF:

0.0624

AC:

301

AN:

4820

European-Finnish (FIN)

AF:

0.101

AC:

1069

AN:

10578

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9278

AN:

67994

Other (OTH)

AF:

0.144

AC:

304

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

915

1830

2745

3660

4575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.138

Hom.:

1629

Bravo

AF:

0.139

Asia WGS

AF:

0.106

AC:

369

AN:

3478

EpiCase

AF:

0.140

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 16, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

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 -

Immunodeficiency 104

Benign:3

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. -

Nov 14, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.495C>T (p.His165=) variant (NM_002185.5) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 5398/35384) of the c.495C>T variant in IL7R is 0.1491 for Latino/Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 2363 homozygous individuals were reported (BS2_Supporting is met). In summary, this variant is classified as Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BP7, BA1, and BS2_Supporting. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.5

(source)

DANN

Benign

0.43

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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