rs3135932

Positions:

• chr11-117993348-A-G

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.475A>G​(p.Ser159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,704 control chromosomes in the GnomAD database, including 20,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S159S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1413 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19048 hom.)
• Consequence: IL10RA NM_001558.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.415

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=0.0017890036).
• BP6: Variant 11-117993348-A-G is Benign according to our data. Variant chr11-117993348-A-G is described in ClinVar as [Benign]. Clinvar id is 197197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117993348-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL10RA	NM_001558.4	c.475A>G	p.Ser159Gly	missense_variant	4/7	ENST00000227752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL10RA	ENST00000227752.8	c.475A>G	p.Ser159Gly	missense_variant	4/7	1	NM_001558.4	P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17411 AN: 152176 Hom.: 1415 Cov.: 33

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00403

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.130 AC: 32588 AN: 251430 Hom.: 2721 AF XY: 0.136 AC XY: 18539 AN XY: 135882

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0519

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.00218

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.154 AC: 225212 AN: 1461410 Hom.: 19048 Cov.: 34 AF XY: 0.155 AC XY: 113025 AN XY: 727054

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.0550

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.114 AC: 17399 AN: 152294 Hom.: 1413 Cov.: 33 AF XY: 0.115 AC XY: 8546 AN XY: 74454

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.0728

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.00404

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.102

Alfa AF: 0.147 Hom.: 3692

Bravo AF: 0.0976

TwinsUK AF: 0.166 AC: 614

ALSPAC AF: 0.171 AC: 658

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.165 AC: 1415

ExAC AF: 0.132 AC: 15971

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.153

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inflammatory bowel disease 28 Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.048
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.75	P
Vest4		0.084
MPC		0.20
ClinPred		0.0043	T
GERP RS		2.0
Varity_R		0.24
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3135932; hg19: chr11-117864063;