5-35857018-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP4PM2_SupportingPM3_Supporting

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

5
8
6

Clinical Significance

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

Conservation

PhyloP100: 4.04
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
IL7RNM_002185.5 linkc.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
IL7RENST00000303115.8 linkc.41T>C p.Leu14Ser missense_variant Exon 1 of 8 1 NM_002185.5 ENSP00000306157.3 P16871-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458178
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725708
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Immunodeficiency 104 Pathogenic:1Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGenApr 01, 2024NM_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). -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 01, 2021ACMG 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
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
.;.;T;.;.
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.69
T;T;T;T;T
M_CAP
Benign
0.083
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Uncertain
2.7
.;.;M;M;.
PrimateAI
Benign
0.44
T
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
D
GERP RS
5.5
Varity_R
0.23
gMVP
0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1759661333; hg19: chr5-35857120; API