rs4845374

Variant names:

• chr1-154454471-T-A
• rs4845374
• NM_000565.4:c.1067-17T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-154454471-T-A
• chr1-154454471-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000565.4(IL6R):​c.1067-17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,294,146 control chromosomes in the GnomAD database, including 19,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2621 hom., cov: 31)
  • Exomes 𝑓: 0.19 (16526 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-154454471-T-A is Benign according to our data. Variant chr1-154454471-T-A is described in ClinVar as Benign. ClinVar VariationId is 1165317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.1067-17T>A		intron_variant	Intron 8 of 9	ENST00000368485.8	NP_000556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IL6R	ENST00000368485.8	c.1067-17T>A		intron_variant	Intron 8 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27232 AN: 150300 Hom.: 2614 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.189 AC: 36479 AN: 192926 AF XY: 0.188

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.188 AC: 215211 AN: 1143738 Hom.: 16526 Cov.: 21 AF XY: 0.186 AC XY: 107445 AN XY: 576474

African (AFR) AF: 0.280 AC: 7839 AN: 28028

American (AMR) AF: 0.105 AC: 3865 AN: 36980

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4285 AN: 22336

East Asian (EAS) AF: 0.119 AC: 4122 AN: 34772

South Asian (SAS) AF: 0.178 AC: 13043 AN: 73420

European-Finnish (FIN) AF: 0.178 AC: 8308 AN: 46638

Middle Eastern (MID) AF: 0.207 AC: 1025 AN: 4952

European-Non Finnish (NFE) AF: 0.193 AC: 163551 AN: 847970

Other (OTH) AF: 0.189 AC: 9173 AN: 48642

GnomAD4 genome AF: 0.181 AC: 27266 AN: 150408 Hom.: 2621 Cov.: 31 AF XY: 0.178 AC XY: 13082 AN XY: 73406

African (AFR) AF: 0.248 AC: 10146 AN: 40906

American (AMR) AF: 0.124 AC: 1873 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 643 AN: 3458

East Asian (EAS) AF: 0.105 AC: 536 AN: 5128

South Asian (SAS) AF: 0.177 AC: 843 AN: 4768

European-Finnish (FIN) AF: 0.153 AC: 1578 AN: 10286

Middle Eastern (MID) AF: 0.169 AC: 49 AN: 290

European-Non Finnish (NFE) AF: 0.164 AC: 11082 AN: 67500

Other (OTH) AF: 0.163 AC: 338 AN: 2078

Alfa AF: 0.174 Hom.: 287

Bravo AF: 0.180

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 18. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.30
DANN	Benign	0.84
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4845374; hg19: chr1-154426947; COSMIC: COSV59818794; COSMIC: COSV59818794;