9-34658535-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001142784.3(IL11RA):c.662C>T(p.Pro221Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P221R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IL11RA NM_001142784.3 missense
• Clinical Significance: Not reported in ClinVar
• 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
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL11RA	NM_001142784.3	c.662C>T	p.Pro221Leu	missense_variant	8/13	ENST00000441545.7
IL11RA	NR_052010.2	n.749C>T		non_coding_transcript_exon_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL11RA	ENST00000441545.7	c.662C>T	p.Pro221Leu	missense_variant	8/13	5	NM_001142784.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
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	0.74	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	-9.5	D;D;D;D;D;.
REVEL	Pathogenic	0.87
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		0.95
MutPred		0.78		Loss of catalytic residue at P220 (P = 0.0117);Loss of catalytic residue at P220 (P = 0.0117);.;Loss of catalytic residue at P220 (P = 0.0117);Loss of catalytic residue at P220 (P = 0.0117);Loss of catalytic residue at P220 (P = 0.0117);
MVP		0.97
MPC		0.81
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;