NM_002185.5:c.1241C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_002185.5(IL7R):c.1241C>T (p.Thr414Met) missense variant occurs at a frequency too high for the disease. The filtering allele frequency based on the South Asian population (upper bound of 95% CI of 1076/30502 observed alleles) is 0.03353 in gnomAD v2.1.1, which is above the SCID-VCEP BA1 threshold (>0.00566). Also, 46 adult homozygous individuals with this variant are present in gnomAD v2.1.1 (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. Criteria applied: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160123/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.0059 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 144 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:5O:1

Conservation

PhyloP100: -0.111

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 104
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
Omenn syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IL7R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
IL7R	NM_002185.5 link	c.1241C>T	p.Thr414Met	missense_variant	Exon 8 of 8	ENST00000303115.8	NP_002176.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 link	c.1241C>T	p.Thr414Met	missense_variant	Exon 8 of 8	1	NM_002185.5	ENSP00000306157.3

Frequencies

GnomAD3 genomes

AF:

0.00585

AC:

890

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.0300

Gnomad SAS

AF:

0.0323

Gnomad FIN

AF:

0.00679

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.0103

AC:

2573

AN:

250690

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.0267

Gnomad FIN exome

AF:

0.00766

Gnomad NFE exome

AF:

0.00475

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.00711

AC:

10387

AN:

1460904

Hom.:

144

Cov.:

AF XY:

0.00816

AC XY:

5930

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33434

American (AMR)

AF:

0.00226

AC:

101

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

351

AN:

26066

East Asian (EAS)

AF:

0.0358

AC:

1422

AN:

39682

South Asian (SAS)

AF:

0.0372

AC:

3209

AN:

86186

European-Finnish (FIN)

AF:

0.00847

AC:

452

AN:

53370

Middle Eastern (MID)

AF:

0.0239

AC:

138

AN:

5764

European-Non Finnish (NFE)

AF:

0.00371

AC:

4127

AN:

1111360

Other (OTH)

AF:

0.00880

AC:

531

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

603

1206

1809

2412

3015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00586

AC:

893

AN:

152268

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41546

American (AMR)

AF:

0.00431

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3468

East Asian (EAS)

AF:

0.0301

AC:

156

AN:

5184

South Asian (SAS)

AF:

0.0326

AC:

157

AN:

4820

European-Finnish (FIN)

AF:

0.00679

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00475

AC:

323

AN:

68026

Other (OTH)

AF:

0.00997

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00579

Hom.:

Bravo

AF:

0.00516

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.0107

AC:

1302

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00539

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 10, 2023

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_002185.5(IL7R):c.1241C>T (p.Thr414Met) missense variant occurs at a frequency too high for the disease. The filtering allele frequency based on the South Asian population (upper bound of 95% CI of 1076/30502 observed alleles) is 0.03353 in gnomAD v2.1.1, which is above the SCID-VCEP BA1 threshold (>0.00566). Also, 46 adult homozygous individuals with this variant are present in gnomAD v2.1.1 (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. Criteria applied: BA1 and BS2_Supporting (SCID VCEP specifications version 1.0).

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Mar 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-0.11

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Uncertain

0.015

Sift4G

Uncertain

0.031

Vest4

0.047

ClinPred

0.020

GERP RS

-1.1

Varity_R

0.020

gMVP

0.40

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over