NM_002185.5:c.394C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP1_StrongPS3_SupportingPP4PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_002185.5(IL7R):c.394C>T is a missense variant predicted to cause substitution of Proline by Serine at amino acid 132 (p.Pro132Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002236 (1/44718) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). 3 patients (PMID:11023514) were found homozygous for this mutation (1 pt.) (PM3_met). 2 patients (Pt. 85 and 86) were found homozygous for this mutation in a consanguineous family (PMID : 35482138). 3 patients with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total : 1.25 pts) (PMID:11023514,PP4_met). In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R. (PMID:11023514, PS3_supporting). The variant has been reported to segregate with SCID in 3 affected members from 2 families (PP1_strong).In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PM3_met,PP4_met,PS3_supporting,PP1_strong(VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA124399/MONDO:0012163/119

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

13

3

3

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 4.47

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS3

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

PM2

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

PM3

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

PP1

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 rank	MANE	Protein	UniProt
IL7R	NM_002185.5 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 4 of 8	ENST00000303115.8	NP_002176.2	P16871-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL7R	ENST00000303115.8 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 4 of 8	1	NM_002185.5	ENSP00000306157.3		P16871-1
IL7R	ENST00000506850.5 link	c.394C>T	p.Pro132Ser	missense_variant	Exon 4 of 6	2		ENSP00000421207.1		P16871-3
IL7R	ENST00000514217.5 link	n.394C>T		non_coding_transcript_exon_variant	Exon 4 of 6	2		ENSP00000427688.1		B8YG18

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251170

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

1

AN:

1460652

Hom.:

0

Cov.:

29

AF XY:

0.00000138

AC XY:

1

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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

Cov.:

33

ExAC

AF:

0.00000824

AC:

1

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Pathogenic:2

Oct 15, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 24, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_002185.5(IL7R):c.394C>T is a missense variant predicted to cause substitution of Proline by Serine at amino acid 132 (p.Pro132Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002236 (1/44718) in Admixed American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). 3 patients (PMID: 11023514) were found homozygous for this mutation (1 pt.) (PM3_met). 2 patients (Pt. 85 and 86) were found homozygous for this mutation in a consanguineous family (PMID : 35482138). 3 patients with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total : 1.25 pts) (PMID: 11023514,PP4_met). In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R. (PMID: 11023514, PS3_supporting). The variant has been reported to segregate with SCID in 3 affected members from 2 families (PP1_strong). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting,PM3_met,PP4_met,PS3_supporting,PP1_strong(VCEP specifications version 1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

D

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

26

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.85

D

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.32

D

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.87

D

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.43

T

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.76

MutPred

0.79

Gain of ubiquitination at K128 (P = 0.1504);Gain of ubiquitination at K128 (P = 0.1504);

MVP

0.99

MPC

0.11

ClinPred

1.0

D

GERP RS

5.6

Varity_R

0.97

gMVP

0.81

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.

Other links and lift over

dbSNP: rs104893894; hg19: chr5-35871172; COSMIC: COSV57411685; COSMIC: COSV57411685;