5-35871171-C-T

Variant names:

• chr5-35871171-C-T
• rs2228141
• NM_002185.5:c.495C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP7 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.495C>T (p.His165=) variant (NM_002185.5) is a synonymous (silent) variant that is not predicted by SpliceAI and varSEAK to impact splicing (BP7).The filtering allele frequency (the lower threshold of the 95% CI of 5398/35384) of the c.495C>T variant in IL7R is 0.1491 for Latino/Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 2363 homozygous individuals were reported (BS2_Supporting is met).In summary, this variant is classified as Benign for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): BP7, BA1, and BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA291241/MONDO:0012163/119

• Frequency:
  • Genomes: 𝑓 0.13 (1327 hom., cov: 33)
  • Exomes 𝑓: 0.13 (13845 hom.)
• Consequence: IL7R NM_002185.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.446
• Publications: 31 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: Benign. The variant received -10 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.495C>T	p.His165His	synonymous	Exon 4 of 8	NP_002176.2
	IL7R	NM_001437964.1		c.495C>T	p.His165His	synonymous	Exon 4 of 7	NP_001424893.1
	IL7R	NM_001410734.1		c.495C>T	p.His165His	synonymous	Exon 4 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.495C>T	p.His165His	synonymous	Exon 4 of 8	ENSP00000306157.3	P16871-1
	IL7R	ENST00000877114.1		c.495C>T	p.His165His	synonymous	Exon 4 of 7	ENSP00000547173.1
	IL7R	ENST00000506850.5	TSL:2	c.495C>T	p.His165His	synonymous	Exon 4 of 6	ENSP00000421207.1	P16871-3

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19986 AN: 151976 Hom.: 1327 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0632

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.127 AC: 31804 AN: 251042 AF XY: 0.122

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0991

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.134 AC: 195901 AN: 1457346 Hom.: 13845 Cov.: 31 AF XY: 0.132 AC XY: 95373 AN XY: 725238

African (AFR) AF: 0.128 AC: 4264 AN: 33390

American (AMR) AF: 0.154 AC: 6886 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3117 AN: 26104

East Asian (EAS) AF: 0.133 AC: 5283 AN: 39648

South Asian (SAS) AF: 0.0614 AC: 5293 AN: 86212

European-Finnish (FIN) AF: 0.100 AC: 5364 AN: 53396

Middle Eastern (MID) AF: 0.140 AC: 806 AN: 5748

European-Non Finnish (NFE) AF: 0.141 AC: 156724 AN: 1107898

Other (OTH) AF: 0.136 AC: 8164 AN: 60242

GnomAD4 genome AF: 0.131 AC: 19978 AN: 152094 Hom.: 1327 Cov.: 33 AF XY: 0.128 AC XY: 9523 AN XY: 74348

African (AFR) AF: 0.132 AC: 5464 AN: 41464

American (AMR) AF: 0.143 AC: 2188 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3472

East Asian (EAS) AF: 0.145 AC: 747 AN: 5168

South Asian (SAS) AF: 0.0624 AC: 301 AN: 4820

European-Finnish (FIN) AF: 0.101 AC: 1069 AN: 10578

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9278 AN: 67994

Other (OTH) AF: 0.144 AC: 304 AN: 2114

Alfa AF: 0.138 Hom.: 1629

Bravo AF: 0.139

Asia WGS AF: 0.106 AC: 369 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.139

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.5
DANN	Benign	0.43
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2228141; hg19: chr5-35871273; COSMIC: COSV57406213; COSMIC: COSV57406213;