rs4252303

Positions:

• chr11-117989590-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001558.4(IL10RA):​c.337G>A​(p.Val113Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00926 in 1,614,108 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (93 hom.)
• Consequence: IL10RA NM_001558.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.16

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=0.004027009).
• BP6: Variant 11-117989590-G-A is Benign according to our data. Variant chr11-117989590-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 302544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-117989590-G-A is described in Lovd as [Benign]. Variant chr11-117989590-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00628 (957/152282) while in subpopulation AMR AF= 0.0098 (150/15302). AF 95% confidence interval is 0.00902. There are 5 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL10RA	NM_001558.4	c.337G>A	p.Val113Ile	missense_variant	3/7	ENST00000227752.8	NP_001549.2
IL10RA	XM_047426882.1	c.277G>A	p.Val93Ile	missense_variant	3/7		XP_047282838.1
IL10RA	XM_047426884.1	c.-81+1088G>A		intron_variant			XP_047282840.1
IL10RA	NR_026691.2	n.541G>A		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL10RA	ENST00000227752.8	c.337G>A	p.Val113Ile	missense_variant	3/7	1	NM_001558.4	ENSP00000227752	P1

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 957 AN: 152164 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00963

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00680 AC: 1709 AN: 251400 Hom.: 11 AF XY: 0.00652 AC XY: 886 AN XY: 135902

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00430

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00956 AC: 13982 AN: 1461826 Hom.: 93 Cov.: 32 AF XY: 0.00939 AC XY: 6827 AN XY: 727216

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00885

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00470

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.00798

GnomAD4 genome AF: 0.00628 AC: 957 AN: 152282 Hom.: 5 Cov.: 33 AF XY: 0.00611 AC XY: 455 AN XY: 74468

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00980

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00367

Gnomad4 NFE AF: 0.00963

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00855 Hom.: 12

Bravo AF: 0.00660

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00701 AC: 851

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inflammatory bowel disease 28 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 17, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	IL10RA: BP4, BS1, BS2 -

IL10RA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0010
DANN	Benign	0.66
DEOGEN2	Benign	0.096	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.14
Sift	Benign	0.40	T
Sift4G	Benign	0.55	T
Polyphen		0.0030	B
Vest4		0.066
MVP		0.29
MPC		0.17
ClinPred		0.0097	T
GERP RS		-9.9
Varity_R		0.12
gMVP		0.18

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: rs4252303; hg19: chr11-117860305; COSMIC: COSV57139876; COSMIC: COSV57139876;