1-154435237-T-C

Variant names:

• chr1-154435237-T-C
• rs7521458
• NM_000565.4:c.807+81T>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.807+81T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 1,375,794 control chromosomes in the GnomAD database, including 109,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (9392 hom., cov: 32)
  • Exomes 𝑓: 0.40 (100581 hom.)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.43
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-154435237-T-C is Benign according to our data. Variant chr1-154435237-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688005.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL6R	NM_000565.4	c.807+81T>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.807+81T>C		intron_variant	Intron 5 of 9	1	NM_000565.4	ENSP00000357470.3

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49648 AN: 151974 Hom.: 9391 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.400 AC: 489137 AN: 1223702 Hom.: 100581 AF XY: 0.397 AC XY: 242170 AN XY: 610166

African (AFR) AF: 0.129 AC: 3683 AN: 28616

American (AMR) AF: 0.551 AC: 20714 AN: 37572

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 8272 AN: 21060

East Asian (EAS) AF: 0.404 AC: 15406 AN: 38126

South Asian (SAS) AF: 0.314 AC: 22911 AN: 72996

European-Finnish (FIN) AF: 0.304 AC: 13972 AN: 45936

Middle Eastern (MID) AF: 0.375 AC: 1934 AN: 5160

European-Non Finnish (NFE) AF: 0.415 AC: 382581 AN: 922236

Other (OTH) AF: 0.378 AC: 19664 AN: 52000

GnomAD4 genome AF: 0.326 AC: 49649 AN: 152092 Hom.: 9392 Cov.: 32 AF XY: 0.322 AC XY: 23930 AN XY: 74360

African (AFR) AF: 0.137 AC: 5692 AN: 41488

American (AMR) AF: 0.495 AC: 7558 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1339 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1975 AN: 5170

South Asian (SAS) AF: 0.295 AC: 1425 AN: 4824

European-Finnish (FIN) AF: 0.288 AC: 3048 AN: 10590

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27300 AN: 67966

Other (OTH) AF: 0.347 AC: 730 AN: 2104

Alfa AF: 0.187 Hom.: 711

Bravo AF: 0.341

Asia WGS AF: 0.306 AC: 1067 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 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.14
DANN	Benign	0.14
PhyloP100		-2.4
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: rs7521458; hg19: chr1-154407713; COSMIC: COSV59818705; COSMIC: COSV59818705;