5-35876198-T-G

Position:

chr5-35876198-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1092T>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause the substitution of Aspartic Acid by Glutamic Acid at amino acid 364 (p.Asp364Glu).The filtering allele frequency (the lower threshold of the 95% CI of 1584/91068 alleles) of the c.1092T>G variant in IL7R is 0.01668 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 35 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/CA160129/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.00051 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 32 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:3O:1

Conservation

PhyloP100: -1.75

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:

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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.1092T>G	p.Asp364Glu	missense_variant	8/8	ENST00000303115.8	NP_002176.2	P16871-1
IL7R	NM_001410734.1 linkuse as main transcript	c.*209T>G		3_prime_UTR_variant	7/7		NP_001397663.1
IL7R	NR_120485.3 linkuse as main transcript	n.916T>G		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.1092T>G	p.Asp364Glu	missense_variant	8/8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0160

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00222

AC:

558

AN:

251008

Hom.:

AF XY:

0.00296

AC XY:

401

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.00109

AC:

1590

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1136

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00123

GnomAD4 genome

AF:

0.000512

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000660

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.00241

AC:

293

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Apr 03, 2024	The c.1092T>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause the substitution of Aspartic Acid by Glutamic Acid at amino acid 364 (p.Asp364Glu). The filtering allele frequency (the lower threshold of the 95% CI of 1584/91068 alleles) of the c.1092T>G variant in IL7R is 0.01668 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 35 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) -

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

Benign

0.097

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0040

DANN

Benign

0.37

DEOGEN2

Benign

0.12

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.42

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.14

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.0080

MutPred

0.12

Loss of catalytic residue at D364 (P = 0.031);

MVP

0.23

MPC

0.014

ClinPred

0.0076

GERP RS

-11

Varity_R

0.045

gMVP

0.087

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