9-34655220-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001142784.3(IL11RA):c.3G>A(p.Met1?) variant causes a start lost, splice region change. The variant allele was found at a frequency of 0.00000686 in 1,457,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: IL11RA NM_001142784.3 start_lost, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.58

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34655220-G-A is Pathogenic according to our data. Variant chr9-34655220-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 493489.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.3G>A	p.Met1?	start_lost, splice_region_variant	2/13	ENST00000441545.7
IL11RA	NR_052010.2	n.90G>A		splice_region_variant, non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL11RA	ENST00000441545.7	c.3G>A	p.Met1?	start_lost, splice_region_variant	2/13	5	NM_001142784.3	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 243780 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132052

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457300 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 6 AN XY: 724900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.27	T;.;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.74	N;N;N;N;N;N;N;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.029	D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;D
Polyphen		0.95	.;P;P;.;.;P;.;.;.
Vest4		0.85, 0.85, 0.85, 0.85
MutPred		0.52		.;Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);Loss of MoRF binding (P = 0.0978);
MVP		0.90
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1470928377; hg19: chr9-34655217;