1-154449591-T-C

Variant names:

• chr1-154449591-T-C
• rs4845625
• NM_000565.4:c.997-320T>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.997-320T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 152,064 control chromosomes in the GnomAD database, including 27,943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.60 (27943 hom., cov: 32)
• Consequence: IL6R NM_000565.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.71
• Publications: 133 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 1-154449591-T-C is Benign according to our data. Variant chr1-154449591-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	NM_000565.4	MANE Select	c.997-320T>C		intron	N/A	NP_000556.1
	IL6R	NM_001382769.1		c.997-320T>C		intron	N/A	NP_001369698.1
	IL6R	NM_001382770.1		c.1090-320T>C		intron	N/A	NP_001369699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.997-320T>C		intron	N/A	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.997-320T>C		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000476006.5	TSL:3	c.811-320T>C		intron	N/A	ENSP00000423668.1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90945 AN: 151946 Hom.: 27901 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.599 AC: 91043 AN: 152064 Hom.: 27943 Cov.: 32 AF XY: 0.588 AC XY: 43722 AN XY: 74316

African (AFR) AF: 0.705 AC: 29239 AN: 41492

American (AMR) AF: 0.653 AC: 9992 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2094 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2402 AN: 5158

South Asian (SAS) AF: 0.410 AC: 1977 AN: 4822

European-Finnish (FIN) AF: 0.447 AC: 4722 AN: 10558

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.568 AC: 38610 AN: 67964

Other (OTH) AF: 0.582 AC: 1229 AN: 2110

Alfa AF: 0.582 Hom.: 99037

Bravo AF: 0.624

Asia WGS AF: 0.452 AC: 1575 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0060
DANN	Benign	0.20
PhyloP100		-4.7
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: rs4845625; hg19: chr1-154422067;