19-55368341-C-G

Position:

• chr19-55368341-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000641.4(IL11):​c.298G>C​(p.Asp100His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IL11 NM_000641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0420

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL11	NM_000641.4	c.298G>C	p.Asp100His	missense_variant	4/5	ENST00000264563.7	NP_000632.1
IL11	NM_001267718.2	c.61G>C	p.Asp21His	missense_variant	3/4		NP_001254647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL11	ENST00000264563.7	c.298G>C	p.Asp100His	missense_variant	4/5	1	NM_000641.4	ENSP00000264563.1
IL11	ENST00000585513.1	c.298G>C	p.Asp100His	missense_variant	4/5	1		ENSP00000467355.1
IL11	ENST00000590625.5	c.61G>C	p.Asp21His	missense_variant	3/4	2		ENSP00000465705.1
IL11	ENST00000587093.1	c.61G>C	p.Asp21His	missense_variant	3/3	2		ENSP00000468663.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446216 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 716592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2023

The c.298G>C (p.D100H) alteration is located in exon 4 (coding exon 4) of the IL11 gene. This alteration results from a G to C substitution at nucleotide position 298, causing the aspartic acid (D) at amino acid position 100 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.96	D;.;D;.
Vest4		0.56
MutPred		0.77		Loss of stability (P = 0.0279);.;Loss of stability (P = 0.0279);.;
MVP		0.66
MPC		0.55
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.76
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs950285638; hg19: chr19-55879709;