5-35857018-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2_SupportingPM3_SupportingPP4

This summary comes from the ClinGen Evidence Repository: NM_002185.5(IL7R):c.41T>C is a missense variant predicted to cause substitution of Leucine by Serine at amino acid 14 (p.Leu14Ser). The highest population minor allele frequency in gnomAD v4 is 0.00001160 (1/86214 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient P1 was found homozygous for this mutation (0.5 pt.) (PM3_supporting) (PMID:33599911).Patient with SCID (0.5 pt.) and exome sequencing conducted (0.5 pt.) (total :1 pt.) (PP4) (PMID:33599911).In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_supporting, PP4(VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA359425853/MONDO:0012163/119

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IL7R
NM_002185.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1

Conservation

PhyloP100: 4.04

Publications

0 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: 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

IL7R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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.

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.41T>C	p.Leu14Ser	missense_variant	Exon 1 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.41T>C	p.Leu14Ser	missense_variant	Exon 1 of 8	1	NM_002185.5	ENSP00000306157.3		P16871-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458178

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725708

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109274

Other (OTH)

AF:

0.00

AC:

AN:

60292

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Immunodeficiency 104

Pathogenic:1Uncertain:1

Apr 01, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_002185.5(IL7R):c.41T>C is a missense variant predicted to cause substitution of Leucine by Serine at amino acid 14 (p.Leu14Ser). The highest population minor allele frequency in gnomAD v4 is 0.00001160 (1/86214 alleles) in South Asian population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient P1 was found homozygous for this mutation (0.5 pt.) (PM3_supporting) (PMID: 33599911).Patient with SCID (0.5 pt.) and exome sequencing conducted (0.5 pt.) (total :1 pt.) (PP4) (PMID: 33599911). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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_supporting, PP4(VCEP specifications version 1). -

Dec 01, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 supporting, PM2 moderate, PM3 moderate, PP4 supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.69

T;T;T;T;T

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.7

.;.;M;M;.

PhyloP100

4.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.3

D;D;D;N;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.82, 0.81, 0.80

MutPred

0.61

Loss of stability (P = 0.0108);Loss of stability (P = 0.0108);Loss of stability (P = 0.0108);Loss of stability (P = 0.0108);Loss of stability (P = 0.0108);

MVP

0.95

MPC

0.11

ClinPred

0.99

GERP RS

5.5

PromoterAI

0.082

Neutral

(source)

Varity_R

0.23

gMVP

0.79

Mutation Taster

=2/98

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over