X-28789324-C-T

Position:

• chrX-28789324-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_014271.4(IL1RAPL1):​c.-20C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,133,249 control chromosomes in the GnomAD database, including 1 homozygotes. There are 353 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., 19 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (1 hom. 334 hem.)
• Consequence: IL1RAPL1 NM_014271.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.01

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant X-28789324-C-T is Benign according to our data. Variant chrX-28789324-C-T is described in ClinVar as [Benign]. Clinvar id is 368187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL1RAPL1	NM_014271.4	c.-20C>T		5_prime_UTR_variant	2/11	ENST00000378993.6	NP_055086.1
IL1RAPL1	XM_017029240.2	c.-20C>T		5_prime_UTR_variant	2/11		XP_016884729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL1RAPL1	ENST00000378993.6	c.-20C>T		5_prime_UTR_variant	2/11	1	NM_014271.4	ENSP00000368278	P1

Frequencies

GnomAD3 genomes AF: 0.000779 AC: 87 AN: 111641 Hom.: 0 Cov.: 23 AF XY: 0.000562 AC XY: 19 AN XY: 33809

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000785 AC: 143 AN: 182217 Hom.: 0 AF XY: 0.000944 AC XY: 63 AN XY: 66769

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.000538

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000960

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00102 AC: 1045 AN: 1021564 Hom.: 1 Cov.: 19 AF XY: 0.00108 AC XY: 334 AN XY: 310192

Gnomad4 AFR exome AF: 0.000199

Gnomad4 AMR exome AF: 0.000741

Gnomad4 ASJ exome AF: 0.000476

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000779 AC: 87 AN: 111685 Hom.: 0 Cov.: 23 AF XY: 0.000561 AC XY: 19 AN XY: 33863

Gnomad4 AFR AF: 0.0000974

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00109 Hom.: 8

Bravo AF: 0.00102

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2020

- -

Intellectual disability, X-linked 21 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200878713; hg19: chrX-28807441; COSMIC: COSV100150718;