NM_000565.4:c.1066+1029G>T

Variant names:

• chr1-154451009-G-T
• rs4845626
• NM_000565.4:c.1066+1029G>T

Variant summary

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

The NM_000565.4(IL6R):​c.1066+1029G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,228 control chromosomes in the GnomAD database, including 4,771 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 0.23 (4771 hom., cov: 32)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307
• Publications: 21 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.1066+1029G>T		intron	N/A	NP_000556.1
	IL6R	NM_001382769.1		c.1066+1029G>T		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.1159+1029G>T		intron	N/A	NP_001369699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.1066+1029G>T		intron	N/A	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.1066+1029G>T		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000858510.1		c.1159+1029G>T		intron	N/A	ENSP00000528569.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34712 AN: 152110 Hom.: 4740 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.229 AC: 34793 AN: 152228 Hom.: 4771 Cov.: 32 AF XY: 0.226 AC XY: 16828 AN XY: 74426

African (AFR) AF: 0.389 AC: 16146 AN: 41508

American (AMR) AF: 0.147 AC: 2251 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3470

East Asian (EAS) AF: 0.105 AC: 545 AN: 5188

South Asian (SAS) AF: 0.181 AC: 874 AN: 4832

European-Finnish (FIN) AF: 0.168 AC: 1779 AN: 10602

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11843 AN: 68016

Other (OTH) AF: 0.216 AC: 456 AN: 2112

Alfa AF: 0.182 Hom.: 1599

Bravo AF: 0.231

Asia WGS AF: 0.186 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs4845626; hg19: chr1-154423485;