rs3135932

Variant names:

• chr11-117993348-A-G
• rs3135932
• NM_001558.4:c.475A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:6
• Conservation: PhyloP100: 0.415
• Publications: 61 publications found

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]

IL10RA Gene-Disease associations (from GenCC):

• inflammatory bowel disease 28

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• IL10-related early-onset inflammatory bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 197197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001558.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RA	NM_001558.4	MANE Select	c.475A>G	p.Ser159Gly	missense	Exon 4 of 7	NP_001549.2	Q13651
	IL10RA	NM_001440423.1		c.28A>G	p.Ser10Gly	missense	Exon 2 of 5	NP_001427352.1
	IL10RA	NR_026691.2		n.679A>G		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL10RA	ENST00000227752.8	TSL:1 MANE Select	c.475A>G	p.Ser159Gly	missense	Exon 4 of 7	ENSP00000227752.4	Q13651
	IL10RA	ENST00000529924.6	TSL:1	n.2053A>G		non_coding_transcript_exon	Exon 3 of 6
	IL10RA	ENST00000951964.1		c.469A>G	p.Ser157Gly	missense	Exon 4 of 7	ENSP00000622023.1

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

GnomAD2 exomes AF: 0.130 AC: 32588 AN: 251430 AF XY: 0.136

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 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

African (AFR) AF: 0.0220 AC: 735 AN: 33478

American (AMR) AF: 0.0550 AC: 2461 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3367 AN: 26136

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39678

South Asian (SAS) AF: 0.162 AC: 13937 AN: 86246

European-Finnish (FIN) AF: 0.203 AC: 10859 AN: 53414

Middle Eastern (MID) AF: 0.108 AC: 623 AN: 5768

European-Non Finnish (NFE) AF: 0.166 AC: 184612 AN: 1111588

Other (OTH) AF: 0.142 AC: 8586 AN: 60378

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

African (AFR) AF: 0.0285 AC: 1187 AN: 41578

American (AMR) AF: 0.0728 AC: 1113 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3468

East Asian (EAS) AF: 0.00404 AC: 21 AN: 5194

South Asian (SAS) AF: 0.158 AC: 761 AN: 4830

European-Finnish (FIN) AF: 0.199 AC: 2106 AN: 10594

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11414 AN: 68012

Other (OTH) AF: 0.102 AC: 216 AN: 2114

Alfa AF: 0.147 Hom.: 7407

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Inflammatory bowel disease 28 (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.41
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
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3135932; hg19: chr11-117864063; COSMIC: COSV107188502;