rs138482569

Variant names:

• chr5-35860921-C-T
• rs138482569
• NM_002185.5:c.152C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-35860921-C-T
• chr5-35860921-C-A
• chr5-35860921-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: NM_002185.5(IL7R):c.152C>T is a missense variant predicted to cause substitution of Serine by Leucine at amino acid 51 (p.Ser51Leu). The filtering allele frequency (the lower threshold of the 95% CI of 110/74978) of the c.152C>T variant in IL7R is 0.001270 for African/African American chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00126) for BS1, and therefore meets this criterion (BS1). To our knowledge, this variant has not been reported in the literature in individuals affected with IL7R-related conditions or in functional studies.As per SCID VCEP specifications, 1 Strong criteria is enough to reach Likely Benign classification. In summary, this variant meets the criteria to be classified as a Likely Benign 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: BS1 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA160084/MONDO:0012163/119

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2 O:1
• Conservation: PhyloP100: -0.368
• Publications: 6 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	NM_002185.5	MANE Select	c.152C>T	p.Ser51Leu	missense	Exon 2 of 8	NP_002176.2
	IL7R	NM_001437964.1		c.152C>T	p.Ser51Leu	missense	Exon 2 of 7	NP_001424893.1
	IL7R	NM_001410734.1		c.152C>T	p.Ser51Leu	missense	Exon 2 of 7	NP_001397663.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL7R	ENST00000303115.8	TSL:1 MANE Select	c.152C>T	p.Ser51Leu	missense	Exon 2 of 8	ENSP00000306157.3	P16871-1
	IL7R	ENST00000877114.1		c.152C>T	p.Ser51Leu	missense	Exon 2 of 7	ENSP00000547173.1
	IL7R	ENST00000506850.5	TSL:2	c.152C>T	p.Ser51Leu	missense	Exon 2 of 6	ENSP00000421207.1	P16871-3

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251152 AF XY: 0.000133

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1460898 Hom.: 0 Cov.: 30 AF XY: 0.0000715 AC XY: 52 AN XY: 726870

African (AFR) AF: 0.00161 AC: 54 AN: 33440

American (AMR) AF: 0.000112 AC: 5 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39694

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111162

Other (OTH) AF: 0.000265 AC: 16 AN: 60372

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74426

African (AFR) AF: 0.00135 AC: 56 AN: 41538

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.000552

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Immunodeficiency 104 (3)
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.72
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.37
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.18
Sift	Benign	0.30	T
Sift4G	Benign	0.59	T
Polyphen		0.29	B
Vest4		0.086
MVP		0.63
MPC		0.015
ClinPred		0.0044	T
GERP RS		-0.80
Varity_R		0.073
gMVP		0.53
Mutation Taster		=91/9	polymorphism

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: rs138482569; hg19: chr5-35861023; COSMIC: COSV57410477;