NM_000565.4:c.1073A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000565.4(IL6R):c.1073A>C(p.Asp358Ala) 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. D358V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.32 ( 9020 hom., cov: 30)

Exomes 𝑓: 0.39 ( 113611 hom. )

Consequence

IL6R
NM_000565.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 0.519

Publications

611 publications found

Variant links:

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

IL6R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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_000565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.387

AC XY:

279734

AN XY:

723282

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

15809

31618

47427

63236

79045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13778

27556

41334

55112

68890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.321

AC:

48588

AN:

151420

Hom.:

9020

Cov.:

AF XY:

0.317

AC XY:

23400

AN XY:

73922

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1566

3131

4697

6262

7828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

IL6R-related disorder (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

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.34

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.48

MetaRNN

Benign

0.00012

MetaSVM

Benign

-0.98

PhyloP100

0.52

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.091

Sift

Benign

0.24

Sift4G

Benign

0.34

Polyphen

0.12

Vest4

0.29

MPC

0.33

ClinPred

0.0088

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over