5-35871070-C-T

Variant names:

• chr5-35871070-C-T
• rs104893894
• NM_002185.5:c.394C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM3 PM2_Supporting PP1_Strong PP4 PS3_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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 4.47
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 104

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002185.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	NM_002185.5	MANE Select	c.394C>T	p.Pro132Ser	missense	Exon 4 of 8	NP_002176.2
	IL7R	NM_001437964.1		c.394C>T	p.Pro132Ser	missense	Exon 4 of 7	NP_001424893.1
	IL7R	NM_001410734.1		c.394C>T	p.Pro132Ser	missense	Exon 4 of 7	NP_001397663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	ENST00000303115.8	TSL:1 MANE Select	c.394C>T	p.Pro132Ser	missense	Exon 4 of 8	ENSP00000306157.3
	IL7R	ENST00000506850.5	TSL:2	c.394C>T	p.Pro132Ser	missense	Exon 4 of 6	ENSP00000421207.1
	IL7R	ENST00000514217.5	TSL:2	n.394C>T		non_coding_transcript_exon	Exon 4 of 6	ENSP00000427688.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110898

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Submissions by phenotype

Immunodeficiency 104 Pathogenic:2

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).

Oct 15, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.79		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
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

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