chr5-35874473-C-T

Position:

chr5-35874473-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2_SupportingBA1

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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
IL7R	NM_002185.5 linkuse as main transcript	c.731C>T	p.Thr244Ile	missense_variant	6/8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 linkuse as main transcript	c.731C>T	p.Thr244Ile	missense_variant	6/8	1	NM_002185.5	ENSP00000306157	P1	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

GnomAD3 exomes

AF:

0.232

AC:

58330

AN:

251338

Hom.:

7344

AF XY:

0.236

AC XY:

32122

AN XY:

135836

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 SAS exome

AF:

0.210

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

Gnomad4 AFR exome

AF:

0.0993

Gnomad4 AMR exome

AF:

0.183

Gnomad4 ASJ exome

AF:

0.228

Gnomad4 EAS exome

AF:

0.180

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.338

Gnomad4 NFE exome

AF:

0.269

Gnomad4 OTH exome

AF:

0.243

GnomAD4 genome

AF:

0.210

AC:

31942

AN:

152076

Hom.:

3852

Cov.:

AF XY:

0.212

AC XY:

15763

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.176

Gnomad4 ASJ

AF:

0.232

Gnomad4 EAS

AF:

0.166

Gnomad4 SAS

AF:

0.201

Gnomad4 FIN

AF:

0.345

Gnomad4 NFE

AF:

0.265

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.248

Hom.:

12208

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

Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	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). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	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	Fulgent Genetics, Fulgent Genetics	Aug 25, 2021	- -

not specified

Benign:3Other:1

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: Frequency -
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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2Other:1

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	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28964592, 21833088, 27188999, 17660817, 18721276, 24728327, 21670443, 17660530, 17660816, 21629267, 19523791, 19626041) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.77

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

MutationTaster

Benign

1.0

P;P;P

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

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