5-35873604-G-T

Position:

chr5-35873604-G-T

Variant summary

Our verdict is Pathogenic. Variant got 4 ACMG points: 4P and 0B. PP4PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported.PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant.This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met.The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160099/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4O:1

Conservation

PhyloP100: 5.76

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 Pathogenic. Variant got 4 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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.662G>T	p.Ser221Ile	missense_variant	5/8	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.662G>T	p.Ser221Ile	missense_variant	5/8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported. PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant. This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met. The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 221 of the IL7R protein (p.Ser221Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 17201233, 18641513; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 134528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL7R protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 20, 2023

Variant summary: IL7R c.662G>T (p.Ser221Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes. c.662G>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency (example, Lebet_2008, Ponda_2006). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17201233, 18641513). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(S201I); This variant is associated with the following publications: (PMID: 8617735, 15661025, 19141282, 18641513, 31817502, 17201233) -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.4

M;M;.

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.86

MutPred

0.84

Gain of catalytic residue at S221 (P = 0.0674);Gain of catalytic residue at S221 (P = 0.0674);.;

MVP

0.98

MPC

0.11

ClinPred

1.0

GERP RS

6.0

Varity_R

0.93

gMVP

0.83

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