Genetic Variant IL11RA:p.Pro221Leu (chr9-34658535-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.29

Publications

7 publications found

Variant links:

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]

IL11RA Gene-Disease associations (from GenCC):

craniosynostosis and dental anomalies
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

IL11RA links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

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 VariationId is 30137.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142784.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL11RA	NM_001142784.3	MANE Select	c.662C>T	p.Pro221Leu	missense	Exon 8 of 13	NP_001136256.1	Q14626-1
	IL11RA	NR_052010.2		n.749C>T		non_coding_transcript_exon	Exon 8 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IL11RA	ENST00000441545.7	TSL:5 MANE Select	c.662C>T	p.Pro221Leu	missense	Exon 8 of 13	ENSP00000394391.3	Q14626-1
IL11RA	ENST00000318041.13	TSL:1	c.662C>T	p.Pro221Leu	missense	Exon 8 of 13	ENSP00000326500.8	Q14626-1
IL11RA	ENST00000602473.5	TSL:1	c.662C>T	p.Pro221Leu	missense	Exon 7 of 10	ENSP00000473647.1	Q14626-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

PhyloP100

5.3

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-9.5

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.78

Loss of catalytic residue at P220 (P = 0.0117)

MVP

0.97

MPC

0.81

ClinPred

1.0

GERP RS

5.2

Varity_R

0.92

gMVP

0.94

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over