rs11567735

Positions:

chr5-35867423-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: NM_002185.5(IL7R):c.339A>C is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 113 (p.Glu113Asp). The filtering allele frequency (the lower threshold of the 95% CI of 308/75016) of the c.339A>C variant in IL7R is 0.003481 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1).To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1_met (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA3231920/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 1.48

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:

IL7R (HGNC:):

IL7R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS1

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.339A>C	p.Glu113Asp	missense_variant	3/8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 linkuse as main transcript	c.339A>C	p.Glu113Asp	missense_variant	3/8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000307

AC:

AN:

250790

Hom.:

AF XY:

0.000221

AC XY:

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461144

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.00404

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00118

AC:

179

AN:

152284

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00416

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.00118

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 09, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 10, 2024	NM_002185.5(IL7R):c.339A>C is a missense variant predicted to cause substitution of Glutamic Acid by Aspartic Acid at amino acid 113 (p.Glu113Asp). The filtering allele frequency (the lower threshold of the 95% CI of 308/75016) of the c.339A>C variant in IL7R is 0.003481 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS1_met (VCEP specifications version 1). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

7.0

DANN

Benign

0.96

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.53

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.0060

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.61

N;N;N

REVEL

Benign

0.088

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.0040

B;.;.

Vest4

0.11

MutPred

0.27

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.78

MPC

0.014

ClinPred

0.0085

GERP RS

3.2

Varity_R

0.18

gMVP

0.24

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