rs147153824

chr5-35874520-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_002185.5(IL7R):c.778G>A(p.Ala260Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. A260A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 0.750

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0071740746).
• BP6: Variant 5-35874520-G-A is Benign according to our data. Variant chr5-35874520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 418258.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00127 (194/152196) while in subpopulation AFR AF= 0.00453 (188/41492). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL7R	NM_002185.5	c.778G>A	p.Ala260Thr	missense_variant	6/8	ENST00000303115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8	c.778G>A	p.Ala260Thr	missense_variant	6/8	1	NM_002185.5	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000318 AC: 80 AN: 251396 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135878

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1460850 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 726816

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000450

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74424

Gnomad4 AFR AF: 0.00453

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000228 Hom.: 0

Bravo AF: 0.00165

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000436 AC: 53

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Immunodeficiency 104 Uncertain:1 Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.778G>A (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 260 (p.Ala260Thr). The filtering allele frequency (the lower threshold of the 95% CI of 115/24962) of the c.778G>A variant in IL7R is 0.003885 in exomes and 0.003267 in genomes (no homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1). The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1. (VCEP specifications version 1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	IL7R NM_002185.4 exon 6 p.Ala260Thr (c.778G>A): This variant has not been reported in the literature but is present in 0.4% (115/24962) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-35874622-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:418258). This variant amino acid Threonine (Thr) is present in 5 species (Chinese hamster, Golden hamster, Elephant, Elephant shrew, Manatee) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.20
Sift	Benign	0.41	T
Sift4G	Benign	0.30	T
Polyphen		0.0060	B
Vest4		0.052
MVP		0.99
MPC		0.016
ClinPred		0.015	T
GERP RS		3.9
Varity_R		0.027
gMVP		0.41

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: rs147153824; hg19: chr5-35874622;