5-35876337-A-G

Position:

chr5-35876337-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS2_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The c.1231A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 411 (p.Thr411Ala).The filtering allele frequency (the lower threshold of the 95% CI of 329/24950) of the c.1231A>G variant in IL7R is 0.01172 in exomes (4 homozygous reported) and 0.01126 in genomes (1 homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1). Five (05) adult homozygous individuals with this variant are present in gnomAD v2.1.1 (African/African American)(BS2_Supporting). The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160117/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.0036 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: -0.0440

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 -5 ACMG points.

BS1

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

BS2

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.1231A>G	p.Thr411Ala	missense_variant	8/8	ENST00000303115.8	NP_002176.2	P16871-1
IL7R	NM_001410734.1 linkuse as main transcript	c.*348A>G		3_prime_UTR_variant	7/7		NP_001397663.1
IL7R	NR_120485.3 linkuse as main transcript	n.1055A>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.1231A>G	p.Thr411Ala	missense_variant	8/8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000957

AC:

240

AN:

250800

Hom.:

AF XY:

0.000583

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000319

AC:

466

AN:

1461052

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.00364

AC:

555

AN:

152314

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0129

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000587

Hom.:

Bravo

AF:

0.00404

ESP6500AA

AF:

0.0138

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00127

AC:

154

ClinVar

Significance: Likely benign

Submissions summary: Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Benign:3

Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.1231A>G (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 411 (p.Thr411Ala). The filtering allele frequency (the lower threshold of the 95% CI of 329/24950) of the c.1231A>G variant in IL7R is 0.01172 in exomes (4 homozygous reported) and 0.01126 in genomes (1 homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1). Five (05) adult homozygous individuals with this variant are present in gnomAD v2.1.1 (African/African American)(BS2_Supporting). The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1 and BS2_Supporting. (VCEP specifications version 1). -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	IL7R: BP4, BS1, BS2 -

not specified

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2017	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, no classification provided	reference population	ITMI	Sep 19, 2013	- -

IL7R-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.6

DANN

Benign

0.97

DEOGEN2

Benign

0.15

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.019

Sift

Benign

0.21

Sift4G

Benign

0.60

Polyphen

0.13

Vest4

0.036

MVP

0.53

MPC

0.018

ClinPred

0.0068

GERP RS

3.3

Varity_R

0.044

gMVP

0.38

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