rs1494555

Positions:

Variant summary

Our verdict is Benign. Variant got -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

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:13O:2

Conservation

PhyloP100: 0.106

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL7R	NM_002185.5 linkuse as main transcript	c.412G>A	p.Val138Ile	missense_variant	4/8	ENST00000303115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8 linkuse as main transcript	c.412G>A	p.Val138Ile	missense_variant	4/8	1	NM_002185.5	P1	P16871-1
IL7R	ENST00000506850.5 linkuse as main transcript	c.412G>A	p.Val138Ile	missense_variant	4/6	2			P16871-3
IL7R	ENST00000514217.5 linkuse as main transcript	c.412G>A	p.Val138Ile	missense_variant, NMD_transcript_variant	4/6	2

Frequencies

GnomAD3 genomes

AF:

0.714

AC:

108457

AN:

151966

Hom.:

39716

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.639

AC:

160614

AN:

251166

Hom.:

53025

AF XY:

0.639

AC XY:

86677

AN XY:

135734

show subpopulations

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 SAS exome

AF:

0.553

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.:

AF XY:

0.664

AC XY:

481763

AN XY:

725596

show subpopulations

Gnomad4 AFR exome

AF:

0.883

Gnomad4 AMR exome

AF:

0.515

Gnomad4 ASJ exome

AF:

0.643

Gnomad4 EAS exome

AF:

0.479

Gnomad4 SAS exome

AF:

0.554

Gnomad4 FIN exome

AF:

0.740

Gnomad4 NFE exome

AF:

0.680

Gnomad4 OTH exome

AF:

0.663

GnomAD4 genome

AF:

0.714

AC:

108523

AN:

152084

Hom.:

39736

Cov.:

AF XY:

0.709

AC XY:

52719

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.871

Gnomad4 AMR

AF:

0.580

Gnomad4 ASJ

AF:

0.653

Gnomad4 EAS

AF:

0.476

Gnomad4 SAS

AF:

0.543

Gnomad4 FIN

AF:

0.744

Gnomad4 NFE

AF:

0.676

Gnomad4 OTH

AF:

0.687

Alfa

AF:

0.675

Hom.:

84524

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:1Benign:13Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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. -

Immunodeficiency 104

Uncertain:1Benign:5

Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	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). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 20952689, 21326139, 18687755) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.65

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

LIST_S2

Benign

0.13

T;T

MetaRNN

Benign

0.0000029

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.35

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

GERP RS

-1.6

Varity_R

0.11

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over