rs2229114

Variant names:

• chr11-117999163-C-T
• rs2229114
• NM_001558.4:c.1259C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001558.4(IL10RA):​c.1259C>T​(p.Ser420Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,614,092 control chromosomes in the GnomAD database, including 1,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S420S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (116 hom., cov: 33)
  • Exomes 𝑓: 0.041 (1431 hom.)
• Consequence: IL10RA NM_001558.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.738
• Publications: 35 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: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.0020552278).
• BP6: Variant 11-117999163-C-T is Benign according to our data. Variant chr11-117999163-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 302556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0321 (4888/152330) while in subpopulation NFE AF = 0.0484 (3291/68036). AF 95% confidence interval is 0.047. There are 116 homozygotes in GnomAd4. There are 2386 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 116 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL10RA	NM_001558.4	c.1259C>T	p.Ser420Leu	missense_variant	Exon 7 of 7	ENST00000227752.8	NP_001549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10RA	ENST00000227752.8	c.1259C>T	p.Ser420Leu	missense_variant	Exon 7 of 7	1	NM_001558.4	ENSP00000227752.4

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4888 AN: 152212 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.00815

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0157

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0321 AC: 8051 AN: 251132 AF XY: 0.0318

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.0303

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0163

Gnomad NFE exome AF: 0.0494

Gnomad OTH exome AF: 0.0413

GnomAD4 exome AF: 0.0413 AC: 60410 AN: 1461762 Hom.: 1431 Cov.: 35 AF XY: 0.0407 AC XY: 29604 AN XY: 727164

African (AFR) AF: 0.00741 AC: 248 AN: 33480

American (AMR) AF: 0.0311 AC: 1391 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 1204 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00670 AC: 578 AN: 86258

European-Finnish (FIN) AF: 0.0185 AC: 989 AN: 53392

Middle Eastern (MID) AF: 0.0385 AC: 222 AN: 5766

European-Non Finnish (NFE) AF: 0.0481 AC: 53485 AN: 1111930

Other (OTH) AF: 0.0380 AC: 2292 AN: 60382

GnomAD4 genome AF: 0.0321 AC: 4888 AN: 152330 Hom.: 116 Cov.: 33 AF XY: 0.0320 AC XY: 2386 AN XY: 74476

African (AFR) AF: 0.00813 AC: 338 AN: 41580

American (AMR) AF: 0.0478 AC: 731 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4822

European-Finnish (FIN) AF: 0.0157 AC: 167 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0484 AC: 3291 AN: 68036

Other (OTH) AF: 0.0397 AC: 84 AN: 2116

Alfa AF: 0.0451 Hom.: 247

Bravo AF: 0.0330

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0491 AC: 422

ExAC AF: 0.0318 AC: 3865

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0510

EpiControl AF: 0.0521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IL10RA: BP4, BS1, BS2 -

Inflammatory bowel disease 28 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.74
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.049
Sift	Benign	0.072	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.32	B
Vest4		0.026
MPC		0.20
ClinPred		0.0077	T
GERP RS		1.8
Varity_R		0.042
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2229114; hg19: chr11-117869878;