Genetic Variant IL11:p.Arg112His (chr19-55368304-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000641.4(IL11):c.335G>A(p.Arg112His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,582,484 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 25 hom., cov: 31)

Exomes 𝑓: 0.023 ( 496 hom. )

Consequence

IL11
NM_000641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.427

Publications

43 publications found

Variant links:

Genes affected

IL11 (HGNC:5966): (interleukin 11) The protein encoded by this gene is a member of the gp130 family of cytokines. These cytokines drive the assembly of multisubunit receptor complexes, all of which contain at least one molecule of the transmembrane signaling receptor IL6ST (gp130). This cytokine is shown to stimulate the T-cell-dependent development of immunoglobulin-producing B cells. It is also found to support the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

IL11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003406167).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0184 (2803/152200) while in subpopulation SAS AF = 0.0352 (170/4832). AF 95% confidence interval is 0.0309. There are 25 homozygotes in GnomAd4. There are 1365 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IL11	NM_000641.4 link	c.335G>A	p.Arg112His	missense_variant	Exon 4 of 5	ENST00000264563.7	NP_000632.1
IL11	NM_001267718.2 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 4		NP_001254647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
IL11	ENST00000264563.7 link	c.335G>A	p.Arg112His	missense_variant	Exon 4 of 5	1	NM_000641.4	ENSP00000264563.1
IL11	ENST00000585513.1 link	c.335G>A	p.Arg112His	missense_variant	Exon 4 of 5	1		ENSP00000467355.1
IL11	ENST00000590625.5 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 4	2		ENSP00000465705.1
IL11	ENST00000587093.1 link	c.98G>A	p.Arg33His	missense_variant	Exon 3 of 3	2		ENSP00000468663.1

Frequencies

GnomAD3 genomes

AF:

0.0185

AC:

2807

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0349

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0259

Gnomad OTH

AF:

0.0211

GnomAD2 exomes

AF:

0.0209

AC:

4223

AN:

201770

AF XY:

0.0230

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00895

Gnomad ASJ exome

AF:

0.0290

Gnomad EAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.0217

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0228

AC:

32681

AN:

1430284

Hom.:

496

Cov.:

AF XY:

0.0239

AC XY:

16933

AN XY:

708264

show subpopulations

African (AFR)

AF:

0.00298

AC:

AN:

32902

American (AMR)

AF:

0.00952

AC:

388

AN:

40762

Ashkenazi Jewish (ASJ)

AF:

0.0290

AC:

738

AN:

25488

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38128

South Asian (SAS)

AF:

0.0391

AC:

3212

AN:

82172

European-Finnish (FIN)

AF:

0.0248

AC:

1255

AN:

50572

Middle Eastern (MID)

AF:

0.0329

AC:

188

AN:

5708

European-Non Finnish (NFE)

AF:

0.0232

AC:

25380

AN:

1095512

Other (OTH)

AF:

0.0241

AC:

1421

AN:

59040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1676

3352

5027

6703

8379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

932

1864

2796

3728

4660

<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:

0.0184

AC:

2803

AN:

152200

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

1365

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00424

AC:

176

AN:

41540

American (AMR)

AF:

0.0159

AC:

243

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.0352

AC:

170

AN:

4832

European-Finnish (FIN)

AF:

0.0226

AC:

240

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0259

AC:

1763

AN:

67986

Other (OTH)

AF:

0.0209

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

142

284

426

568

710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0226

Hom.:

126

Bravo

AF:

0.0162

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00298

AC:

ESP6500EA

AF:

0.0237

AC:

203

ExAC

AF:

0.0184

AC:

2214

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.86

.;D;D;D

MetaRNN

Benign

0.0034

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;.;L;.

PhyloP100

0.43

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.4

N;.;.;.

REVEL

Benign

0.085

Sift

Benign

0.056

T;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.14

MPC

0.56

ClinPred

0.011

GERP RS

2.9

Varity_R

0.19

gMVP

0.36

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over