rs387906785

chr9-34658535-C-Gchr9-34658535-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001142784.3(IL11RA):c.662C>G(p.Pro221Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: IL11RA NM_001142784.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.29

Genes affected

IL11RA (HGNC:5967): (interleukin 11 receptor subunit alpha) Interleukin 11 is a stromal cell-derived cytokine that belongs to a family of pleiotropic and redundant cytokines that use the gp130 transducing subunit in their high affinity receptors. This gene encodes the IL-11 receptor, which is a member of the hematopoietic cytokine receptor family. This particular receptor is very similar to ciliary neurotrophic factor, since both contain an extracellular region with a 2-domain structure composed of an immunoglobulin-like domain and a cytokine receptor-like domain. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Fibronectin type-III 2 (size 97) in uniprot entity I11RA_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001142784.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 9-34658535-C-G is Pathogenic according to our data. Variant chr9-34658535-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30137.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL11RA	NM_001142784.3	c.662C>G	p.Pro221Arg	missense_variant	8/13	ENST00000441545.7
IL11RA	NR_052010.2	n.749C>G		non_coding_transcript_exon_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL11RA	ENST00000441545.7	c.662C>G	p.Pro221Arg	missense_variant	8/13	5	NM_001142784.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251310 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727234

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: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniosynostosis and dental anomalies Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 22, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;.;D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.6	D;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.98
MutPred		0.80		Loss of catalytic residue at P220 (P = 0.0226);Loss of catalytic residue at P220 (P = 0.0226);.;Loss of catalytic residue at P220 (P = 0.0226);Loss of catalytic residue at P220 (P = 0.0226);Loss of catalytic residue at P220 (P = 0.0226);
MVP		0.97
MPC		0.82
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.95

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: rs387906785; hg19: chr9-34658532;