11-117998788-C-T

Position:

• chr11-117998788-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001558.4(IL10RA):​c.884C>T​(p.Pro295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,614,162 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P295S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (1 hom.)
• Consequence: IL10RA NM_001558.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: -0.203

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007901698).
• BP6: Variant 11-117998788-C-T is Benign according to our data. Variant chr11-117998788-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538051.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr11-117998788-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152286) while in subpopulation NFE AF= 0.00131 (89/68008). AF 95% confidence interval is 0.00109. There are 1 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL10RA	NM_001558.4	c.884C>T	p.Pro295Leu	missense_variant	7/7	ENST00000227752.8	NP_001549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL10RA	ENST00000227752.8	c.884C>T	p.Pro295Leu	missense_variant	7/7	1	NM_001558.4	ENSP00000227752.4

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000768 AC: 193 AN: 251420 Hom.: 0 AF XY: 0.000773 AC XY: 105 AN XY: 135900

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000923 AC: 1350 AN: 1461876 Hom.: 1 Cov.: 31 AF XY: 0.000877 AC XY: 638 AN XY: 727240

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74460

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000964 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000923 AC: 112

EpiCase AF: 0.00142

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inflammatory bowel disease 28 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 295 of the IL10RA protein (p.Pro295Leu). This variant is present in population databases (rs56143179, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with inflammatory bowel disease (PMID: 29248579, 33359885; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 538051). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IL10RA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Feb 13, 2023	The VUS detected here is a missense variant that leads to an exchange of the amino acid proline, which is weakly conserved at the site, for leucine. In the LOVD shared database the variant is listed as VUS or probably benign, in the ClinVar database (e.g. SCV000768990.7) the variant is evaluated as VUS. In the gnomAD population database, an allele frequency of 0.08% is reported for the variant (gnomAD; ALL). An in silico analysis of this variant using the REVEL program suggests that it may be a variant without clinical significance. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	IL10RA: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in a patient with very onset inflammatory bowel disease (Girardelli et al., 2018); This variant is associated with the following publications: (PMID: 29248579) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Aug 15, 2017

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.2
DANN	Benign	0.19
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.027
Sift	Benign	0.45	T
Sift4G	Benign	1.0	T
Polyphen		0.032	B
Vest4		0.071
MVP		0.31
MPC		0.22
ClinPred		0.0016	T
GERP RS		1.1
Varity_R		0.020
gMVP		0.30

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: rs56143179; hg19: chr11-117869503;