rs149161098

chr5-35871185-G-Achr5-35871185-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_002185.5(IL7R):c.509G>A(p.Arg170His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: IL7R NM_002185.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0151822865).
• BP6: Variant 5-35871185-G-A is Benign according to our data. Variant chr5-35871185-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 464437.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000755 (115/152270) while in subpopulation AFR AF= 0.00265 (110/41564). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 55 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.509G>A	p.Arg170His	missense_variant	4/8	ENST00000303115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8	c.509G>A	p.Arg170His	missense_variant	4/8	1	NM_002185.5	P1
IL7R	ENST00000506850.5	c.509G>A	p.Arg170His	missense_variant	4/6	2
IL7R	ENST00000514217.5	c.509G>A	p.Arg170His	missense_variant, NMD_transcript_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000271 AC: 68 AN: 251122 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135738

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000863 AC: 126 AN: 1460492 Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48 AN XY: 726624

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000739 AC XY: 55 AN XY: 74454

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000820

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 104 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.081
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Uncertain	0.34
Sift	Benign	0.10	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.35	B;.
Vest4		0.24
MVP		0.88
MPC		0.015
ClinPred		0.017	T
GERP RS		3.3
Varity_R		0.23
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149161098; hg19: chr5-35871287; COSMIC: COSV100286465; COSMIC: COSV100286465;