rs1494555

Variant names:

• chr5-35871088-G-A
• rs1494555
• NM_002185.5:c.412G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-35871088-G-A
• chr5-35871088-G-C
• chr5-35871088-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: NM_002185.5(IL7R):c.412G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 138 (p.Val138Ile). The filtering allele frequency (the lower threshold of the 95% CI of 65661/74940 alleles) of the c.412G>A variant in IL7R is 0.8743 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1 and therefore meets this criterion (BA1). Additionally, 367924 homozygous have been described.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. Criteria applied: BA1 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA124393/MONDO:0012163/119

• Frequency:
  • Genomes: 𝑓 0.71 (39736 hom., cov: 32)
  • Exomes 𝑓: 0.67 (328188 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:13 O:2
• Conservation: PhyloP100: 0.106
• Publications: 124 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 -8 ACMG points.

• 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	c.412G>A	p.Val138Ile	missense_variant	Exon 4 of 8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8	c.412G>A	p.Val138Ile	missense_variant	Exon 4 of 8	1	NM_002185.5	ENSP00000306157.3
IL7R	ENST00000506850.5	c.412G>A	p.Val138Ile	missense_variant	Exon 4 of 6	2		ENSP00000421207.1
IL7R	ENST00000514217.5	n.412G>A		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000427688.1

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108457 AN: 151966 Hom.: 39716 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.688

GnomAD2 exomes AF: 0.639 AC: 160614 AN: 251166 AF XY: 0.639

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.635

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.738

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.667 AC: 973208 AN: 1458140 Hom.: 328188 Cov.: 36 AF XY: 0.664 AC XY: 481763 AN XY: 725596

African (AFR) AF: 0.883 AC: 29511 AN: 33432

American (AMR) AF: 0.515 AC: 23040 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 16787 AN: 26100

East Asian (EAS) AF: 0.479 AC: 19006 AN: 39672

South Asian (SAS) AF: 0.554 AC: 47790 AN: 86202

European-Finnish (FIN) AF: 0.740 AC: 39532 AN: 53404

Middle Eastern (MID) AF: 0.633 AC: 3645 AN: 5754

European-Non Finnish (NFE) AF: 0.680 AC: 753941 AN: 1108614

Other (OTH) AF: 0.663 AC: 39956 AN: 60244

GnomAD4 genome AF: 0.714 AC: 108523 AN: 152084 Hom.: 39736 Cov.: 32 AF XY: 0.709 AC XY: 52719 AN XY: 74324

African (AFR) AF: 0.871 AC: 36150 AN: 41508

American (AMR) AF: 0.580 AC: 8846 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2265 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2459 AN: 5164

South Asian (SAS) AF: 0.543 AC: 2621 AN: 4824

European-Finnish (FIN) AF: 0.744 AC: 7849 AN: 10552

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.676 AC: 45966 AN: 67988

Other (OTH) AF: 0.687 AC: 1450 AN: 2112

Alfa AF: 0.683 Hom.: 127502

Bravo AF: 0.711

TwinsUK AF: 0.682 AC: 2530

ALSPAC AF: 0.686 AC: 2643

ESP6500AA AF: 0.874 AC: 3851

ESP6500EA AF: 0.680 AC: 5849

ExAC AF: 0.652 AC: 79111

Asia WGS AF: 0.577 AC: 2007 AN: 3478

EpiCase AF: 0.672

EpiControl AF: 0.680

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:13 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6 Other:1

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 83% of patients studied by a panel of primary immunodeficiencies. Number of patients: 79. Only high quality variants are reported. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: 1 paper published in 1998 claimed variant was pathogenic for SCID based on identification in 1 proband. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Immunodeficiency 104 Uncertain:1 Benign:5

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 1998

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_002185.5(IL7R):c.412G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 138 (p.Val138Ile). The filtering allele frequency (the lower threshold of the 95% CI of 65661/74940 alleles) of the c.412G>A variant in IL7R is 0.8743 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1 and therefore meets this criterion (BA1). Additionally, 367924 homozygous have been described. 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. Criteria applied: BA1 (VCEP specifications version 1). -

not provided Benign:2 Other: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: 20952689, 21326139, 18687755) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.062
DANN	Benign	0.28
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.13	T;T
MetaRNN	Benign	0.0000029	T;T
MetaSVM	Benign	-0.97	T
PhyloP100		0.11
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.77	N;N
REVEL	Benign	0.23
Sift	Benign	0.66	T;T
Sift4G	Benign	0.51	T;T
Vest4		0.029
MPC		0.014
ClinPred		0.0036	T
GERP RS		-1.6
Varity_R		0.11
gMVP		0.18
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: rs1494555; hg19: chr5-35871190; COSMIC: COSV57406117; COSMIC: COSV57406117;