chr9-34655299-C-T

Variant names:

• chr9-34655299-C-T
• rs774749917
• NM_001142784.3:c.82C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001142784.3(IL11RA):​c.82C>T​(p.Gln28*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,453,852 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: IL11RA NM_001142784.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.68
• Publications: 0 publications found

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

ENSG00000258728 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34655299-C-T is Pathogenic according to our data. Variant chr9-34655299-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3340644.

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.82C>T	p.Gln28*	stop_gained	Exon 2 of 13	NP_001136256.1	Q14626-1
	IL11RA	NR_052010.2		n.169C>T		non_coding_transcript_exon	Exon 2 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL11RA	ENST00000441545.7	TSL:5 MANE Select	c.82C>T	p.Gln28*	stop_gained	Exon 2 of 13	ENSP00000394391.3	Q14626-1
	IL11RA	ENST00000318041.13	TSL:1	c.82C>T	p.Gln28*	stop_gained	Exon 2 of 13	ENSP00000326500.8	Q14626-1
	IL11RA	ENST00000602473.5	TSL:1	c.82C>T	p.Gln28*	stop_gained	Exon 1 of 10	ENSP00000473647.1	Q14626-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000166 AC: 4 AN: 240388 AF XY: 0.0000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1453852 Hom.: 0 Cov.: 30 AF XY: 0.00000830 AC XY: 6 AN XY: 723176

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.000135 AC: 6 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106256

Other (OTH) AF: 0.00 AC: 0 AN: 60038

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.69	D
PhyloP100		1.7
Vest4		0.78
GERP RS		3.3
PromoterAI		0.028	Neutral
Mutation Taster		=23/177	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774749917; hg19: chr9-34655296; COSMIC: COSV107377032;