1-154454494-A-C

Variant names:

• chr1-154454494-A-C
• rs2228145
• NM_000565.4:c.1073A>C

Variant summary

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

The NM_001382769.1(IL6R):​c.1172A>C​(p.Asp391Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,604,538 control chromosomes in the GnomAD database, including 122,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D391V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (9020 hom., cov: 30)
  • Exomes 𝑓: 0.39 (113611 hom.)
• Consequence: IL6R NM_001382769.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 0.519
• Publications: 611 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 (MetaRNN=1.2167276E-4).
• BP6: Variant 1-154454494-A-C is Benign according to our data. Variant chr1-154454494-A-C is described in ClinVar as Benign. ClinVar VariationId is 14660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382769.1. 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.1073A>C	p.Asp358Ala	missense	Exon 9 of 10	NP_000556.1
	IL6R	NM_001382769.1		c.1172A>C	p.Asp391Ala	missense	Exon 10 of 11	NP_001369698.1
	IL6R	NM_001382770.1		c.1166A>C	p.Asp389Ala	missense	Exon 10 of 11	NP_001369699.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL6R	ENST00000368485.8	TSL:1 MANE Select	c.1073A>C	p.Asp358Ala	missense	Exon 9 of 10	ENSP00000357470.3
	IL6R	ENST00000344086.8	TSL:1	c.1066+4514A>C		intron	N/A	ENSP00000340589.4
	IL6R	ENST00000858510.1		c.1265A>C	p.Asp422Ala	missense	Exon 11 of 12	ENSP00000528569.1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48587 AN: 151302 Hom.: 9020 Cov.: 30

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.379 AC: 94659 AN: 249648 AF XY: 0.376

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.550

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.390 AC: 565992 AN: 1453118 Hom.: 113611 Cov.: 30 AF XY: 0.387 AC XY: 279734 AN XY: 723282

African (AFR) AF: 0.125 AC: 4182 AN: 33406

American (AMR) AF: 0.544 AC: 24232 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 10817 AN: 26078

East Asian (EAS) AF: 0.392 AC: 15549 AN: 39640

South Asian (SAS) AF: 0.307 AC: 26438 AN: 86012

European-Finnish (FIN) AF: 0.293 AC: 15606 AN: 53224

Middle Eastern (MID) AF: 0.365 AC: 2101 AN: 5752

European-Non Finnish (NFE) AF: 0.403 AC: 444872 AN: 1104308

Other (OTH) AF: 0.369 AC: 22195 AN: 60142

GnomAD4 genome AF: 0.321 AC: 48588 AN: 151420 Hom.: 9020 Cov.: 30 AF XY: 0.317 AC XY: 23400 AN XY: 73922

African (AFR) AF: 0.135 AC: 5578 AN: 41212

American (AMR) AF: 0.489 AC: 7425 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1426 AN: 3466

East Asian (EAS) AF: 0.361 AC: 1850 AN: 5118

South Asian (SAS) AF: 0.290 AC: 1390 AN: 4792

European-Finnish (FIN) AF: 0.280 AC: 2926 AN: 10464

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26730 AN: 67876

Other (OTH) AF: 0.343 AC: 723 AN: 2108

Alfa AF: 0.372 Hom.: 28656

Bravo AF: 0.335

TwinsUK AF: 0.424 AC: 1571

ALSPAC AF: 0.425 AC: 1639

ESP6500AA AF: 0.145 AC: 641

ESP6500EA AF: 0.405 AC: 3480

ExAC AF: 0.369 AC: 44828

Asia WGS AF: 0.286 AC: 998 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IL6R-related disorder (1)
-	-	1	not specified (1)
-	-	-	Interleukin 6, serum level of, quantitative trait locus (1)
-	-	-	Soluble interleukin-6 receptor, serum level of, quantitative trait locus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.00012	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.52
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.091
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.12	B
Vest4		0.29
MPC		0.33
ClinPred		0.0088	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.20
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2228145; hg19: chr1-154426970; COSMIC: COSV59816312; COSMIC: COSV59816312;