NM_000565.4:c.949+5451C>T

Variant names:

• chr1-154441561-C-T
• rs4393147
• NM_000565.4:c.949+5451C>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+5451C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 151,926 control chromosomes in the GnomAD database, including 9,381 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 0.33 (9381 hom., cov: 32)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 22 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.949+5451C>T		intron_variant	Intron 6 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.949+5451C>T		intron_variant	Intron 6 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49586 AN: 151808 Hom.: 9380 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.351

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

GnomAD4 genome AF: 0.326 AC: 49590 AN: 151926 Hom.: 9381 Cov.: 32 AF XY: 0.322 AC XY: 23888 AN XY: 74246

African (AFR) AF: 0.138 AC: 5698 AN: 41424

American (AMR) AF: 0.496 AC: 7563 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1339 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1927 AN: 5176

South Asian (SAS) AF: 0.294 AC: 1417 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3020 AN: 10512

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27310 AN: 67956

Other (OTH) AF: 0.347 AC: 732 AN: 2108

Alfa AF: 0.256 Hom.: 1491

Bravo AF: 0.341

Asia WGS AF: 0.294 AC: 1025 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.4
DANN	Benign	0.65
PhyloP100		-0.24
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: rs4393147; hg19: chr1-154414037;