1-154435864-T-C

Variant names:

• chr1-154435864-T-C
• rs4845371
• NM_000565.4:c.808-105T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000565.4(IL6R):​c.808-105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,024,490 control chromosomes in the GnomAD database, including 172,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27385 hom., cov: 33)
  • Exomes 𝑓: 0.57 (145305 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22
• Publications: 36 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-154435864-T-C is Benign according to our data. Variant chr1-154435864-T-C is described in ClinVar as [Benign]. Clinvar id is 2688523.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.808-105T>C		intron_variant	Intron 5 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.808-105T>C		intron_variant	Intron 5 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90444 AN: 152006 Hom.: 27339 Cov.: 33

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.583

GnomAD4 exome AF: 0.574 AC: 500644 AN: 872366 Hom.: 145305 AF XY: 0.570 AC XY: 246975 AN XY: 433444

African (AFR) AF: 0.676 AC: 13543 AN: 20020

American (AMR) AF: 0.660 AC: 12812 AN: 19410

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 8985 AN: 15604

East Asian (EAS) AF: 0.503 AC: 15731 AN: 31244

South Asian (SAS) AF: 0.480 AC: 24250 AN: 50500

European-Finnish (FIN) AF: 0.477 AC: 20941 AN: 43872

Middle Eastern (MID) AF: 0.557 AC: 1494 AN: 2682

European-Non Finnish (NFE) AF: 0.586 AC: 380821 AN: 650232

Other (OTH) AF: 0.569 AC: 22067 AN: 38802

GnomAD4 genome AF: 0.595 AC: 90545 AN: 152124 Hom.: 27385 Cov.: 33 AF XY: 0.586 AC XY: 43585 AN XY: 74340

African (AFR) AF: 0.665 AC: 27622 AN: 41514

American (AMR) AF: 0.659 AC: 10075 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2025 AN: 3472

East Asian (EAS) AF: 0.473 AC: 2444 AN: 5166

South Asian (SAS) AF: 0.483 AC: 2332 AN: 4824

European-Finnish (FIN) AF: 0.458 AC: 4842 AN: 10564

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39157 AN: 67980

Other (OTH) AF: 0.580 AC: 1226 AN: 2114

Alfa AF: 0.582 Hom.: 6797

Bravo AF: 0.617

Asia WGS AF: 0.488 AC: 1701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 80. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.49
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs4845371; hg19: chr1-154408340; COSMIC: COSV59820230; COSMIC: COSV59820230;