1-154427844-A-G

Variant names:

• chr1-154427844-A-G
• rs6687726
• NM_000565.4:c.86-1352A>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.86-1352A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 151,958 control chromosomes in the GnomAD database, including 20,457 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 0.51 (20457 hom., cov: 31)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.417
• Publications: 23 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.608 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.86-1352A>G		intron	N/A	NP_000556.1
	IL6R	NM_001382769.1		c.86-1352A>G		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.86-1352A>G		intron	N/A	NP_001369699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.86-1352A>G		intron	N/A	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.86-1352A>G		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000622330.5	TSL:1	c.86-1352A>G		intron	N/A	ENSP00000477739.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77937 AN: 151840 Hom.: 20451 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.513 AC: 77972 AN: 151958 Hom.: 20457 Cov.: 31 AF XY: 0.506 AC XY: 37585 AN XY: 74288

African (AFR) AF: 0.419 AC: 17339 AN: 41408

American (AMR) AF: 0.619 AC: 9451 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2002 AN: 3470

East Asian (EAS) AF: 0.486 AC: 2503 AN: 5154

South Asian (SAS) AF: 0.460 AC: 2221 AN: 4826

European-Finnish (FIN) AF: 0.440 AC: 4655 AN: 10572

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37941 AN: 67940

Other (OTH) AF: 0.511 AC: 1080 AN: 2112

Alfa AF: 0.529 Hom.: 3337

Bravo AF: 0.529

Asia WGS AF: 0.465 AC: 1620 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.9
DANN	Benign	0.83
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs6687726; hg19: chr1-154400320; COSMIC: COSV59819688; COSMIC: COSV59819688;