rs4845623

Variant names:

• chr1-154443301-A-G
• rs4845623
• NM_000565.4:c.950-4824A>G

Variant summary

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

The NM_000565.4(IL6R):​c.950-4824A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,084 control chromosomes in the GnomAD database, including 17,389 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 0.47 (17389 hom., cov: 33)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.10
• Publications: 51 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 = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.950-4824A>G		intron_variant	Intron 6 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.950-4824A>G		intron_variant	Intron 6 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70845 AN: 151966 Hom.: 17346 Cov.: 33

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.466 AC: 70937 AN: 152084 Hom.: 17389 Cov.: 33 AF XY: 0.457 AC XY: 33988 AN XY: 74332

African (AFR) AF: 0.602 AC: 24979 AN: 41460

American (AMR) AF: 0.551 AC: 8409 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1359 AN: 3468

East Asian (EAS) AF: 0.371 AC: 1920 AN: 5170

South Asian (SAS) AF: 0.299 AC: 1443 AN: 4824

European-Finnish (FIN) AF: 0.302 AC: 3194 AN: 10592

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28081 AN: 67986

Other (OTH) AF: 0.449 AC: 944 AN: 2104

Alfa AF: 0.452 Hom.: 10415

Bravo AF: 0.498

Asia WGS AF: 0.328 AC: 1143 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	0.027
DANN	Benign	0.21
PhyloP100		-2.1
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: rs4845623; hg19: chr1-154415777;