5-35860966-T-C

Position:

chr5-35860966-T-C

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.197T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 66 (p.Ile66Thr). The filtering allele frequency (the lower threshold of the 95% CI of 56371/74906 alleles) of the c.197T>C variant in IL7R is 0.7458 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, 353136 homozygotes 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/CA124390/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.67 ( 34940 hom., cov: 32)

Exomes 𝑓: 0.66 ( 318196 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:12O:2

Conservation

PhyloP100: 0.311

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.197T>C	p.Ile66Thr	missense_variant	2/8	ENST00000303115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8 linkuse as main transcript	c.197T>C	p.Ile66Thr	missense_variant	2/8	1	NM_002185.5	P1	P16871-1

Frequencies

GnomAD3 genomes

AF:

0.673

AC:

102247

AN:

151946

Hom.:

34942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.563

Gnomad ASJ

AF:

0.638

Gnomad EAS

AF:

0.419

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.736

Gnomad MID

AF:

0.624

Gnomad NFE

AF:

0.671

Gnomad OTH

AF:

0.647

GnomAD3 exomes

AF:

0.618

AC:

155256

AN:

251092

Hom.:

49620

AF XY:

0.619

AC XY:

83955

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.753

Gnomad AMR exome

AF:

0.490

Gnomad ASJ exome

AF:

0.621

Gnomad EAS exome

AF:

0.422

Gnomad SAS exome

AF:

0.517

Gnomad FIN exome

AF:

0.731

Gnomad NFE exome

AF:

0.674

Gnomad OTH exome

AF:

0.648

GnomAD4 exome

AF:

0.656

AC:

958630

AN:

1460288

Hom.:

318196

Cov.:

AF XY:

0.652

AC XY:

473998

AN XY:

726542

show subpopulations

Gnomad4 AFR exome

AF:

0.754

Gnomad4 AMR exome

AF:

0.506

Gnomad4 ASJ exome

AF:

0.630

Gnomad4 EAS exome

AF:

0.423

Gnomad4 SAS exome

AF:

0.516

Gnomad4 FIN exome

AF:

0.732

Gnomad4 NFE exome

AF:

0.677

Gnomad4 OTH exome

AF:

0.644

GnomAD4 genome

AF:

0.673

AC:

102273

AN:

152064

Hom.:

34940

Cov.:

AF XY:

0.669

AC XY:

49718

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.752

Gnomad4 AMR

AF:

0.562

Gnomad4 ASJ

AF:

0.638

Gnomad4 EAS

AF:

0.419

Gnomad4 SAS

AF:

0.509

Gnomad4 FIN

AF:

0.736

Gnomad4 NFE

AF:

0.671

Gnomad4 OTH

AF:

0.642

Alfa

AF:

0.665

Hom.:

83748

Bravo

AF:

0.666

TwinsUK

AF:

0.679

AC:

2519

ALSPAC

AF:

0.682

AC:

2628

ESP6500AA

AF:

0.754

AC:

3323

ESP6500EA

AF:

0.674

AC:

5793

ExAC

AF:

0.627

AC:

76188

Asia WGS

AF:

0.524

AC:

1821

AN:

3478

EpiCase

AF:

0.666

EpiControl

AF:

0.674

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	NM_002185.5(IL7R):c.197T>C is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 66 (p.Ile66Thr). The filtering allele frequency (the lower threshold of the 95% CI of 56371/74906 alleles) of the c.197T>C variant in IL7R is 0.7458 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, 353136 homozygotes 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 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:5Other:1

Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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: 21326139, 30377306) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.55

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.25

T;T;T

MetaRNN

Benign

0.0000011

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

2.1

N;N;N

REVEL

Benign

0.091

Sift

Benign

0.88

T;T;T

Sift4G

Benign

0.73

T;T;T

Vest4

0.023

MPC

0.015

ClinPred

0.0014

GERP RS

2.2

Varity_R

0.074

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