rs4252548

Positions:

• chr19-55368304-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (25 hom., cov: 31)
  • Exomes 𝑓: 0.023 (496 hom.)
• Consequence: IL11 NM_000641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.427

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL11	NM_000641.4	c.335G>A	p.Arg112His	missense_variant	4/5	ENST00000264563.7
IL11	NM_001267718.2	c.98G>A	p.Arg33His	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL11	ENST00000264563.7	c.335G>A	p.Arg112His	missense_variant	4/5	1	NM_000641.4	P1
IL11	ENST00000585513.1	c.335G>A	p.Arg112His	missense_variant	4/5	1		P1
IL11	ENST00000590625.5	c.98G>A	p.Arg33His	missense_variant	3/4	2
IL11	ENST00000587093.1	c.98G>A	p.Arg33His	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2807 AN: 152082 Hom.: 26 Cov.: 31

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

GnomAD3 exomes AF: 0.0209 AC: 4223 AN: 201770 Hom.: 63 AF XY: 0.0230 AC XY: 2515 AN XY: 109258

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 SAS exome AF: 0.0375

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.: 33 AF XY: 0.0239 AC XY: 16933 AN XY: 708264

Gnomad4 AFR exome AF: 0.00298

Gnomad4 AMR exome AF: 0.00952

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.0391

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0232

Gnomad4 OTH exome AF: 0.0241

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152200 Hom.: 25 Cov.: 31 AF XY: 0.0183 AC XY: 1365 AN XY: 74394

Gnomad4 AFR AF: 0.00424

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0259

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.0241 Hom.: 44

Bravo AF: 0.0162

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00298 AC: 13

ESP6500EA AF: 0.0237 AC: 203

ExAC AF: 0.0184 AC: 2214

Asia WGS AF: 0.0180 AC: 63 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	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;T;.
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	.;D;D;D
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;L;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.68	T
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	T
GERP RS		2.9
Varity_R		0.19
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs4252548; hg19: chr19-55879672;