Genetic Variant IL7R:p.Cys118Tyr (chr5-35867437-G-A) – ACMG Classification: Pathogenic (6 pts)

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3PM2_SupportingPP1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The missense variant NM_002185.5(IL7R):c.353G>A (p.Cys118Tyr) occurs at a low filtering allele frequency of 0.000009610 in gnomAD v2.1.1 (<0.00004129; PM2_Supporting). At least 14 SCID or Omenn syndrome patients have been reported with this variant in 10 publications (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025, 34153518, 17827065, 24578017, 27833609). Several have highly specific phenotypes which meet criteria for PP4 (PMIDs: 35503492, 24759676) and one patient (PMID:27833609) had sufficient information to meet PP4_moderate; this patient fulfilled clinical and immunological parameters for severe combined immunodeficiency (SCID), with at T-B+NK+ subtype, absence of CD127 expression, and reduced f IL-7 induced pSTAT5 (Y694) in T-cells, which together are highly specific for IL7R-related SCID (PP4_moderate). Additionally, the variant has been reported to segregate with SCID in 2 affected family members from family 2 in PMID:15661025 (PP1). Of the 14 patients, eight patients have been reported homozygous for this variant (PMIDs: 35503492, 34573280, 27593400, 24759676, 16492442,15661025; PM3) and six compound heterozygous; second variants were reported in P19 (PMID:35503492) and the SCID patient reported in Zago CA et al. (PMID:24759676) both harboring c.361dup without confirmation of trans phase (classified Pathogenic by the SCID VCEP; 0.5+0.5pt), the patients reported by Tsilifis C et al. (PMID:34153518) and Butte MJ et al. (PMID:17827065) both harbor c.379+288G>A confirmed in trans (provisionally classified by the SCID VCEP as VUS; 0.25+0.25pt), Case 1 (PMID:24578017) has c.83-2A>T without confirmation of trans phase (provisionally classified as Pathogenic by the SCID VCEP; 0.5pt), and the patient reported by Gallego-Bustos F et al. (PMID:27833609) has c.333T>A confirmed in trans (provisionally classified Likely Pathogenic by the SCID VCEP; 1pt), Total=4pts (PM3_VeryStrong). 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: PM2_supporting, PM3_VeryStrong, PP1, PP4_moderate. (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214043/MONDO:0012163/119

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 1.57

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency 104
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

IL7R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 6 ACMG points.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IL7R	NM_002185.5	MANE Select	c.353G>A	p.Cys118Tyr	missense	Exon 3 of 8	NP_002176.2
IL7R	NM_001437964.1		c.353G>A	p.Cys118Tyr	missense	Exon 3 of 7	NP_001424893.1
IL7R	NM_001410734.1		c.353G>A	p.Cys118Tyr	missense	Exon 3 of 7	NP_001397663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL7R	ENST00000303115.8	TSL:1 MANE Select	c.353G>A	p.Cys118Tyr	missense	Exon 3 of 8	ENSP00000306157.3	P16871-1
IL7R	ENST00000877114.1		c.353G>A	p.Cys118Tyr	missense	Exon 3 of 7	ENSP00000547173.1
IL7R	ENST00000506850.5	TSL:2	c.353G>A	p.Cys118Tyr	missense	Exon 3 of 6	ENSP00000421207.1	P16871-3

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250510

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460758

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.0000672

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111452

Other (OTH)

AF:

0.0000331

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41360

American (AMR)

AF:

0.000197

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67978

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000452

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 104 (4)

not provided (1)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.25

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.58

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.2

PhyloP100

1.6

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.44

Sift

Benign

0.29

Sift4G

Benign

0.17

Polyphen

0.40

Vest4

0.61

MVP

0.88

MPC

0.017

ClinPred

0.68

GERP RS

3.8

Varity_R

0.38

gMVP

0.56

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over