5-35867438-CA-CAA

Position:

chr5-35867438-CA-CAA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP4PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_002185.5(IL7R):c.361dup (p.Ile121AsnfsTer8) frameshift variant in exon 3 creates a premature stop codon in exon 4/5 (upstream of the final 50 nucleotides), which is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in several SCID patients (PMIDs: 35503492, 24759676, 32765500, 28436970, 25046553), at least one of whom was reported with a highly specific phenotype; the diagnosis of SCID was made by criteria of the Primary Immune Deficiency Treatment Consortium in this patient with a T−BlowNK+ (0 CD3+ cells/mm, 300 B cells/mm3, 450 NK cells/mm3) lymphocyte subset profile (PMID:35503492; PP4). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 9/128422 observed alleles) is 0.00002867 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.00004129) and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA357950/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

IL7R
NM_002185.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 1.33

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 10 ACMG points.

PVS1

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

PM2

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.361dupA	p.Ile121fs	frameshift_variant	3/8	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.361dupA	p.Ile121fs	frameshift_variant	3/8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249940

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000106

AC:

155

AN:

1460456

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000527

AC:

AN:

151770

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular and Human Genetics, Baylor College of Medicine	Apr 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jul 16, 2014	segregates with the phenotype in an affected family -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The NM_002185.5(IL7R):c.361dup (p.Ile121AsnfsTer8) frameshift variant in exon 3 creates a premature stop codon in exon 4/5 (upstream of the final 50 nucleotides), which is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in several SCID patients (PMIDs: 35503492, 24759676, 32765500, 28436970, 25046553), at least one of whom was reported with a highly specific phenotype; the diagnosis of SCID was made by criteria of the Primary Immune Deficiency Treatment Consortium in this patient with a T−BlowNK+ (0 CD3+ cells/mm, 300 B cells/mm3, 450 NK cells/mm3) lymphocyte subset profile (PMID: 35503492; PP4). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 9/128422 observed alleles) is 0.00002867 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.00004129) and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PP4. (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Ile121Asnfs*8) in the IL7R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IL7R are known to be pathogenic (PMID: 21664875, 26123418). This variant is present in population databases (rs781000678, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 24759676, 25046553). ClinVar contains an entry for this variant (Variation ID: 224841). For these reasons, this variant has been classified as Pathogenic. -

Multiple sclerosis, susceptibility to, 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 11, 2022

Variant summary: IL7R c.361dupA (p.Ile121AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 249940 control chromosomes (gnomAD). The variant, c.361dupA, has been reported in the literature in multiple compound heterozygous individuals affected with Severe Combined Immunodeficiency (e.g. Bayer_2014, Zago_2014, Dvorak_2017, Stray-Pedersen_2017 and Kwok_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) or likely pathogenic (n=1). 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

Apr 23, 2021

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25046553, 27577878) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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