1-154438479-C-T

Variant names:

• chr1-154438479-C-T
• rs4553185
• NM_000565.4:c.949+2369C>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.949+2369C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 151,412 control chromosomes in the GnomAD database, including 21,424 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 (21424 hom., cov: 31)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113
• Publications: 45 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.618 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.949+2369C>T		intron	N/A	NP_000556.1
	IL6R	NM_001382769.1		c.949+2369C>T		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.949+2369C>T		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.949+2369C>T		intron	N/A	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.949+2369C>T		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000476006.5	TSL:3	c.715+2369C>T		intron	N/A	ENSP00000423668.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 79877 AN: 151294 Hom.: 21411 Cov.: 31

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.565

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.528 AC: 79933 AN: 151412 Hom.: 21424 Cov.: 31 AF XY: 0.520 AC XY: 38470 AN XY: 73942

African (AFR) AF: 0.453 AC: 18698 AN: 41240

American (AMR) AF: 0.628 AC: 9569 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2003 AN: 3472

East Asian (EAS) AF: 0.474 AC: 2443 AN: 5154

South Asian (SAS) AF: 0.480 AC: 2305 AN: 4800

European-Finnish (FIN) AF: 0.447 AC: 4652 AN: 10402

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.565 AC: 38349 AN: 67818

Other (OTH) AF: 0.524 AC: 1097 AN: 2094

Alfa AF: 0.551 Hom.: 11952

Bravo AF: 0.542

Asia WGS AF: 0.473 AC: 1645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.4
DANN	Benign	0.71
PhyloP100		-0.11
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: rs4553185; hg19: chr1-154410955;