NM_000628.5:c.-74C>A

Variant names:

• chr21-33266392-C-A
• rs56368587
• NM_000628.5:c.-74C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000628.5(IL10RB):​c.-74C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,497,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: IL10RB NM_000628.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.692
• Publications: 0 publications found

Genes affected

IL10RB (HGNC:5965): (interleukin 10 receptor subunit beta) The protein encoded by this gene belongs to the cytokine receptor family. It is an accessory chain essential for the active interleukin 10 receptor complex. Coexpression of this and IL10RA proteins has been shown to be required for IL10-induced signal transduction. This gene and three other interferon receptor genes, IFAR2, IFNAR1, and IFNGR2, form a class II cytokine receptor gene cluster located in a small region on chromosome 21. [provided by RefSeq, Jul 2008]

IFNAR2-IL10RB (HGNC:):

IL10RB-DT (HGNC:44303): (IL10RB divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000394 (60/152208) while in subpopulation NFE AF = 0.000765 (52/68018). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL10RB	NM_000628.5	c.-74C>A		5_prime_UTR_variant	Exon 1 of 7	ENST00000290200.7	NP_000619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL10RB	ENST00000290200.7	c.-74C>A		5_prime_UTR_variant	Exon 1 of 7	1	NM_000628.5	ENSP00000290200.2
IFNAR2-IL10RB	ENST00000433395.7	c.710-2002C>A		intron_variant	Intron 7 of 12	5		ENSP00000388223.3

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000522 AC: 703 AN: 1345486 Hom.: 0 Cov.: 24 AF XY: 0.000504 AC XY: 335 AN XY: 665212

African (AFR) AF: 0.000172 AC: 5 AN: 28998

American (AMR) AF: 0.00 AC: 0 AN: 35000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24510

East Asian (EAS) AF: 0.00 AC: 0 AN: 34166

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77532

European-Finnish (FIN) AF: 0.000161 AC: 6 AN: 37314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3968

European-Non Finnish (NFE) AF: 0.000645 AC: 676 AN: 1047816

Other (OTH) AF: 0.000267 AC: 15 AN: 56182

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74370

African (AFR) AF: 0.000145 AC: 6 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000348

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inflammatory bowel disease 25 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.4
DANN	Benign	0.51
PhyloP100		0.69
PromoterAI		0.00020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism

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: rs56368587; hg19: chr21-34638697;