X-29917575-GAGTTTGGGAA-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_014271.4(IL1RAPL1):​c.894_903delTTGGGAAAGT​(p.Trp299ThrfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 22)

Consequence

IL1RAPL1
NM_014271.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.60

Publications

3 publications found
Variant links:
Genes affected
IL1RAPL1 (HGNC:5996): (interleukin 1 receptor accessory protein like 1) The protein encoded by this gene is a member of the interleukin 1 receptor family and is similar to the interleukin 1 accessory proteins. This protein has an N-terminal signal peptide, three extracellular immunoglobulin Ig-like domains, a transmembrane domain, an intracellular Toll/IL-1R domain, and a long C-terminal tail which interacts with multiple signalling molecules. This gene is located at a region on chromosome X that is associated with a non-syndromic form of X-linked intellectual disability. Deletions and mutations in this gene were found in patients with intellectual disability. This gene is expressed at a high level in post-natal brain structures involved in the hippocampal memory system, which suggests a specialized role in the physiological processes underlying memory and learning abilities, and plays a role in synapse formation and stabilization. [provided by RefSeq, Jul 2017]
IL1RAPL1 Gene-Disease associations (from GenCC):
  • intellectual disability, X-linked 21
    Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • non-syndromic X-linked intellectual disability
    Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-29917575-GAGTTTGGGAA-G is Pathogenic according to our data. Variant chrX-29917575-GAGTTTGGGAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 235849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL1RAPL1NM_014271.4 linkc.894_903delTTGGGAAAGT p.Trp299ThrfsTer18 frameshift_variant Exon 7 of 11 ENST00000378993.6 NP_055086.1 Q9NZN1-1X5DNQ7
IL1RAPL1XM_017029240.2 linkc.894_903delTTGGGAAAGT p.Trp299ThrfsTer18 frameshift_variant Exon 7 of 11 XP_016884729.1 Q9NZN1-1X5DNQ7
IL1RAPL1XM_017029241.2 linkc.516_525delTTGGGAAAGT p.Trp173ThrfsTer18 frameshift_variant Exon 5 of 9 XP_016884730.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL1RAPL1ENST00000378993.6 linkc.894_903delTTGGGAAAGT p.Trp299ThrfsTer18 frameshift_variant Exon 7 of 11 1 NM_014271.4 ENSP00000368278.1 Q9NZN1-1

Frequencies

GnomAD3 genomes
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual disability Pathogenic:1
Jul 25, 2014
Diagnostic Laboratory, Strasbourg University Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
9.6
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

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

Publications

Other links and lift over

dbSNP: rs878853146; hg19: chrX-29935692; API