5-35860901-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002185.5(IL7R):c.132C>T(p.Ser44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,613,370 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: IL7R NM_002185.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:7
• Conservation: PhyloP100: -0.209

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 5-35860901-C-T is Benign according to our data. Variant chr5-35860901-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377976.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00418 (636/152212) while in subpopulation AFR AF= 0.0138 (573/41528). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL7R	NM_002185.5	c.132C>T	p.Ser44=	synonymous_variant	2/8	ENST00000303115.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL7R	ENST00000303115.8	c.132C>T	p.Ser44=	synonymous_variant	2/8	1	NM_002185.5	P1

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 635 AN: 152094 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00117 AC: 294 AN: 251166 Hom.: 2 AF XY: 0.000869 AC XY: 118 AN XY: 135746

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000449 AC: 656 AN: 1461158 Hom.: 4 Cov.: 30 AF XY: 0.000410 AC XY: 298 AN XY: 726910

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152212 Hom.: 6 Cov.: 33 AF XY: 0.00400 AC XY: 298 AN XY: 74418

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000972 Hom.: 1

Bravo AF: 0.00494

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Immunodeficiency 104 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2021	- -
Likely benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.132C>T (p.Ser44=) variant (NM_002185.5) variant in IL7R is a synonymous (silent) variant that is not predicted to impact splicing (BP7). The filtering allele frequency (the lower threshold of the 95% CI of 342/24962) of the c.132C>T variant in IL7R is 0.01271 in exomes and 0.01082 in genomes 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). In summary, this variant meets the criteria to be classified as likely benign for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BP7 and BS1. (VCEP specifications version 1). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

IL7R-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

IL7R: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.0
Dann	Benign	0.60

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: rs11567704; hg19: chr5-35861003;