chr1-154427539-G-T

Variant names:

• chr1-154427539-G-T
• rs4845618
• NM_000565.4:c.86-1657G>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.86-1657G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 152,042 control chromosomes in the GnomAD database, including 21,910 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 0.53 (21910 hom., cov: 32)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 59 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

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 (AMR) allele frequency at 95% confidence interval = 0.619 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.86-1657G>T		intron	N/A	NP_000556.1	P08887-1
	IL6R	NM_001382769.1		c.86-1657G>T		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.86-1657G>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.86-1657G>T		intron	N/A	ENSP00000357470.3	P08887-1
	IL6R	ENST00000344086.8	TSL:1	c.86-1657G>T		intron	N/A	ENSP00000340589.4	P08887-2
	IL6R	ENST00000622330.5	TSL:1	c.86-1657G>T		intron	N/A	ENSP00000477739.1	A0A087WTB5

Frequencies

GnomAD3 genomes AF: 0.533 AC: 81009 AN: 151924 Hom.: 21897 Cov.: 32

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.533 AC: 81063 AN: 152042 Hom.: 21910 Cov.: 32 AF XY: 0.526 AC XY: 39067 AN XY: 74322

African (AFR) AF: 0.487 AC: 20197 AN: 41458

American (AMR) AF: 0.629 AC: 9613 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1997 AN: 3462

East Asian (EAS) AF: 0.486 AC: 2516 AN: 5172

South Asian (SAS) AF: 0.461 AC: 2223 AN: 4818

European-Finnish (FIN) AF: 0.440 AC: 4653 AN: 10584

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 37951 AN: 67950

Other (OTH) AF: 0.534 AC: 1128 AN: 2114

Alfa AF: 0.557 Hom.: 62850

Bravo AF: 0.551

Asia WGS AF: 0.471 AC: 1638 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	3.3
DANN	Benign	0.51
PhyloP100		1.2
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: rs4845618; hg19: chr1-154400015;