rs41270321

Positions:

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.1043A>C (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Asparagine by Threonine at amino acid 348 (p.Asn348Thr).The filtering allele frequency (the lower threshold of the 95% CI of 20801/1179968 alleles) of the c.1043A>C variant in IL7R is 0.01743 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, 215 adult homozygous occurrences are described in gnomAD (BS2_Supporting).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/CA160111/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.010 ( 20 hom., cov: 32)

Exomes 𝑓: 0.015 ( 195 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: -2.30

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 -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
IL7R	NM_002185.5 linkuse as main transcript	c.1043A>C	p.Asn348Thr	missense_variant	8/8	ENST00000303115.8	NP_002176.2
IL7R	NM_001410734.1 linkuse as main transcript	c.*160A>C		3_prime_UTR_variant	7/7		NP_001397663.1
IL7R	NR_120485.3 linkuse as main transcript	n.867A>C		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 linkuse as main transcript	c.1043A>C	p.Asn348Thr	missense_variant	8/8	1	NM_002185.5	ENSP00000306157	P1	P16871-1
IL7R	ENST00000505093.1 linkuse as main transcript	c.*160A>C		3_prime_UTR_variant	3/3	2		ENSP00000426069
IL7R	ENST00000505875.1 linkuse as main transcript	n.341A>C		non_coding_transcript_exon_variant	2/2	2
IL7R	ENST00000514217.5 linkuse as main transcript	c.*237A>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	2		ENSP00000427688

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1550

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00792

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0137

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.0102

AC:

2571

AN:

251032

Hom.:

AF XY:

0.0100

AC XY:

1361

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00608

Gnomad ASJ exome

AF:

0.00994

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00235

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0157

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0151

AC:

22112

AN:

1461802

Hom.:

195

Cov.:

AF XY:

0.0146

AC XY:

10606

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.00633

Gnomad4 ASJ exome

AF:

0.00884

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00263

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0177

Gnomad4 OTH exome

AF:

0.0138

GnomAD4 genome

AF:

0.0102

AC:

1552

AN:

152316

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

707

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00339

Gnomad4 AMR

AF:

0.00784

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0137

Gnomad4 NFE

AF:

0.0158

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.0137

Hom.:

Bravo

AF:

0.00980

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0172

AC:

148

ExAC

AF:

0.0101

AC:

1224

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0155

EpiControl

AF:

0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Immunodeficiency 104

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Apr 03, 2024	The c.1043A>C (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Asparagine by Threonine at amino acid 348 (p.Asn348Thr). The filtering allele frequency (the lower threshold of the 95% CI of 20801/1179968 alleles) of the c.1043A>C variant in IL7R is 0.01743 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, 215 adult homozygous occurrences are described in gnomAD (BS2_Supporting). 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	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. -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

DANN

Benign

0.22

DEOGEN2

Benign

0.11

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.33

REVEL

Benign

0.029

Sift

Benign

0.78

Sift4G

Benign

0.80

Polyphen

0.0010

Vest4

0.052

MPC

0.015

ClinPred

0.000020

GERP RS

-9.9

Varity_R

0.027

gMVP

0.15

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