rs2229113

Positions:

• chr11-117998955-A-G
• chr11-117998955-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001558.4(IL10RA):​c.1051A>G​(p.Arg351Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,612,978 control chromosomes in the GnomAD database, including 406,779 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42313 hom., cov: 33)
  • Exomes 𝑓: 0.70 (364466 hom.)
• Consequence: IL10RA NM_001558.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0510

Genes affected

IL10RA (HGNC:5964): (interleukin 10 receptor subunit alpha) The protein encoded by this gene is a receptor for interleukin 10. This protein is structurally related to interferon receptors. It has been shown to mediate the immunosuppressive signal of interleukin 10, and thus inhibits the synthesis of proinflammatory cytokines. This receptor is reported to promote survival of progenitor myeloid cells through the insulin receptor substrate-2/PI 3-kinase/AKT pathway. Activation of this receptor leads to tyrosine phosphorylation of JAK1 and TYK2 kinases. Two transcript variants, one protein-coding and the other not protein-coding, have been found for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.1809E-7).
• BP6: Variant 11-117998955-A-G is Benign according to our data. Variant chr11-117998955-A-G is described in ClinVar as [Benign]. Clinvar id is 302554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117998955-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL10RA	NM_001558.4	c.1051A>G	p.Arg351Gly	missense_variant	7/7	ENST00000227752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL10RA	ENST00000227752.8	c.1051A>G	p.Arg351Gly	missense_variant	7/7	1	NM_001558.4	P1

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112610 AN: 152016 Hom.: 42261 Cov.: 33

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.743 AC: 186430 AN: 250854 Hom.: 70678 AF XY: 0.735 AC XY: 99685 AN XY: 135580

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.866

Gnomad ASJ exome AF: 0.732

Gnomad EAS exome AF: 0.997

Gnomad SAS exome AF: 0.738

Gnomad FIN exome AF: 0.622

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.728

GnomAD4 exome AF: 0.703 AC: 1027034 AN: 1460844 Hom.: 364466 Cov.: 60 AF XY: 0.702 AC XY: 510298 AN XY: 726520

Gnomad4 AFR exome AF: 0.805

Gnomad4 AMR exome AF: 0.859

Gnomad4 ASJ exome AF: 0.733

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.722

GnomAD4 genome AF: 0.741 AC: 112720 AN: 152134 Hom.: 42313 Cov.: 33 AF XY: 0.741 AC XY: 55104 AN XY: 74352

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.811

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.994

Gnomad4 SAS AF: 0.745

Gnomad4 FIN AF: 0.628

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.751

Alfa AF: 0.704 Hom.: 68148

Bravo AF: 0.760

TwinsUK AF: 0.689 AC: 2554

ALSPAC AF: 0.676 AC: 2607

ESP6500AA AF: 0.808 AC: 3556

ESP6500EA AF: 0.688 AC: 5908

ExAC AF: 0.738 AC: 89558

Asia WGS AF: 0.867 AC: 3011 AN: 3478

EpiCase AF: 0.694

EpiControl AF: 0.692

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 97% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inflammatory bowel disease 28 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2019	This variant is associated with the following publications: (PMID: 17066477, 19772791, 19016528, 18800073, 21654841, 24595243, 23455702, 12759436, 29248579) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.3
DANN	Benign	0.62
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.029
Sift	Benign	0.68	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.27
ClinPred		0.00043	T
GERP RS		1.1
Varity_R		0.036
gMVP		0.17

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: rs2229113; hg19: chr11-117869670; COSMIC: COSV57142373; COSMIC: COSV57142373;