rs41270321

chr5-35876149-A-Cchr5-35876149-A-Gchr5-35876149-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002185.5(IL7R):c.1043A>C(p.Asn348Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,118 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N348S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.015 (195 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Benign reviewed by expert panel B:6 O:1
• Conservation: PhyloP100: -2.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026264489).
• BP6: Variant 5-35876149-A-C is Benign according to our data. Variant chr5-35876149-A-C is described in ClinVar as [Benign]. Clinvar id is 134532.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr5-35876149-A-C is described in Lovd as [Benign]. Variant chr5-35876149-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1552/152316) while in subpopulation NFE AF= 0.0158 (1075/68020). AF 95% confidence interval is 0.015. There are 20 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL7R	NM_002185.5	c.1043A>C	p.Asn348Thr	missense_variant	8/8	ENST00000303115.8
IL7R	NM_001410734.1	c.*160A>C		3_prime_UTR_variant	7/7
IL7R	NR_120485.3	n.867A>C		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8	c.1043A>C	p.Asn348Thr	missense_variant	8/8	1	NM_002185.5	P1
IL7R	ENST00000505093.1	c.*160A>C		3_prime_UTR_variant	3/3	2
IL7R	ENST00000505875.1	n.341A>C		non_coding_transcript_exon_variant	2/2	2
IL7R	ENST00000514217.5	c.*237A>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1550 AN: 152198 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0102 AC: 2571 AN: 251032 Hom.: 24 AF XY: 0.0100 AC XY: 1361 AN XY: 135644

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00608

Gnomad ASJ exome AF: 0.00994

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00235

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0151 AC: 22112 AN: 1461802 Hom.: 195 Cov.: 32 AF XY: 0.0146 AC XY: 10606 AN XY: 727214

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.00633

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.0128

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 152316 Hom.: 20 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74490

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0137 Hom.: 30

Bravo AF: 0.00980

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0172 AC: 148

ExAC AF: 0.0101 AC: 1224

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Immunodeficiency 104 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Apr 03, 2024	The c.1043A>C (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Asparagine by Threonine at amino acid 348 (p.Asn348Thr). The filtering allele frequency (the lower threshold of the 95% CI of 20801/1179968 alleles) of the c.1043A>C variant in IL7R is 0.01743 for European (non-Finnish) chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (>0.00566) for BA1, and therefore meets this criterion (BA1). Additionally, 215 adult homozygous occurrences are described in gnomAD (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1) -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.0010
Dann	Benign	0.22
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.029
Sift	Benign	0.78	T
Sift4G	Benign	0.80	T
Polyphen		0.0010	B
Vest4		0.052
MPC		0.015
ClinPred		0.000020	T
GERP RS		-9.9
Varity_R		0.027
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs41270321; hg19: chr5-35876251; COSMIC: COSV57414714; COSMIC: COSV57414714;