NM_000565.4:c.-208G>A

Variant names:

• chr1-154405422-G-A
• rs4845617
• NM_000565.4:c.-208G>A

Variant summary

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

The NM_000565.4(IL6R):​c.-208G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 533,660 control chromosomes in the GnomAD database, including 40,960 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 0.38 (11390 hom., cov: 34)
  • Exomes 𝑓: 0.39 (29570 hom.)
• Consequence: IL6R NM_000565.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.652
• Publications: 54 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-AS1 (HGNC:53716): (IL6R antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 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.-208G>A		5_prime_UTR	Exon 1 of 10	NP_000556.1	P08887-1
	IL6R	NM_001382769.1		c.-208G>A		5_prime_UTR	Exon 1 of 11	NP_001369698.1
	IL6R	NM_001382770.1		c.-208G>A		5_prime_UTR	Exon 1 of 11	NP_001369699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.-208G>A		5_prime_UTR	Exon 1 of 10	ENSP00000357470.3	P08887-1
	IL6R	ENST00000344086.8	TSL:1	c.-208G>A		5_prime_UTR	Exon 1 of 9	ENSP00000340589.4	P08887-2
	IL6R	ENST00000622330.5	TSL:1	c.-208G>A		5_prime_UTR	Exon 1 of 7	ENSP00000477739.1	A0A087WTB5

Frequencies

GnomAD3 genomes AF: 0.382 AC: 58108 AN: 152056 Hom.: 11382 Cov.: 34

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.359

GnomAD4 exome AF: 0.391 AC: 149201 AN: 381486 Hom.: 29570 Cov.: 4 AF XY: 0.386 AC XY: 78153 AN XY: 202536

African (AFR) AF: 0.315 AC: 2342 AN: 7426

American (AMR) AF: 0.453 AC: 4519 AN: 9966

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 4155 AN: 11328

East Asian (EAS) AF: 0.482 AC: 11526 AN: 23908

South Asian (SAS) AF: 0.330 AC: 12414 AN: 37586

European-Finnish (FIN) AF: 0.451 AC: 12981 AN: 28802

Middle Eastern (MID) AF: 0.314 AC: 544 AN: 1732

European-Non Finnish (NFE) AF: 0.387 AC: 92260 AN: 238298

Other (OTH) AF: 0.377 AC: 8460 AN: 22440

GnomAD4 genome AF: 0.382 AC: 58131 AN: 152174 Hom.: 11390 Cov.: 34 AF XY: 0.386 AC XY: 28700 AN XY: 74396

African (AFR) AF: 0.327 AC: 13593 AN: 41526

American (AMR) AF: 0.442 AC: 6763 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1178 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2443 AN: 5148

South Asian (SAS) AF: 0.323 AC: 1559 AN: 4830

European-Finnish (FIN) AF: 0.454 AC: 4813 AN: 10598

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26549 AN: 67980

Other (OTH) AF: 0.359 AC: 759 AN: 2116

Alfa AF: 0.388 Hom.: 14362

Bravo AF: 0.381

Asia WGS AF: 0.367 AC: 1275 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.65
PromoterAI		-0.094	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4845617; hg19: chr1-154377898;