rs4329505

Variant names:

• chr1-154459944-T-C
• rs4329505
• NM_000565.4:c.1161-5190T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000565.4(IL6R):​c.1161-5190T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 151,966 control chromosomes in the GnomAD database, including 4,212 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4212 hom., cov: 32)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 50 publications found

Genes affected

IL6R (HGNC:6019): (interleukin 6 receptor) This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9. [provided by RefSeq, Aug 2020]

IL6R Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 5, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.1161-5190T>C		intron_variant	Intron 9 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.1161-5190T>C		intron_variant	Intron 9 of 9	1	NM_000565.4	ENSP00000357470.3
IL6R	ENST00000344086.8	c.1067-5190T>C		intron_variant	Intron 8 of 8	1		ENSP00000340589.4
IL6R	ENST00000502679.1	n.474-5190T>C		intron_variant	Intron 1 of 1	2
IL6R	ENST00000507256.1	n.359-5190T>C		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32500 AN: 151848 Hom.: 4188 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.214 AC: 32565 AN: 151966 Hom.: 4212 Cov.: 32 AF XY: 0.211 AC XY: 15693 AN XY: 74294

African (AFR) AF: 0.365 AC: 15076 AN: 41316

American (AMR) AF: 0.137 AC: 2090 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3470

East Asian (EAS) AF: 0.103 AC: 535 AN: 5184

South Asian (SAS) AF: 0.173 AC: 833 AN: 4826

European-Finnish (FIN) AF: 0.153 AC: 1615 AN: 10584

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11146 AN: 67986

Other (OTH) AF: 0.185 AC: 391 AN: 2110

Alfa AF: 0.182 Hom.: 7885

Bravo AF: 0.217

Asia WGS AF: 0.178 AC: 618 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.44
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs4329505; hg19: chr1-154432420;