X-28789228-G-A

Variant names:

• chrX-28789228-G-A
• rs12009069
• NM_014271.4:c.-24-92G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014271.4(IL1RAPL1):​c.-24-92G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 513,400 control chromosomes in the GnomAD database, including 38,821 homozygotes. There are 79,014 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (7707 hom., 14188 hem., cov: 23)
  • Exomes 𝑓: 0.48 (31114 hom. 64826 hem.)
• Consequence: IL1RAPL1 NM_014271.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.585
• Publications: 0 publications found

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant X-28789228-G-A is Benign according to our data. Variant chrX-28789228-G-A is described in ClinVar as Benign. ClinVar VariationId is 1236336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014271.4. 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
	IL1RAPL1	NM_014271.4	MANE Select	c.-24-92G>A		intron	N/A	NP_055086.1	X5DNQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RAPL1	ENST00000378993.6	TSL:1 MANE Select	c.-24-92G>A		intron	N/A	ENSP00000368278.1	Q9NZN1-1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 48223 AN: 110594 Hom.: 7695 Cov.: 23

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.518

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.632

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.481 AC: 193805 AN: 402755 Hom.: 31114 AF XY: 0.487 AC XY: 64826 AN XY: 133069

African (AFR) AF: 0.336 AC: 3893 AN: 11589

American (AMR) AF: 0.519 AC: 12375 AN: 23864

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 7726 AN: 13123

East Asian (EAS) AF: 0.456 AC: 10656 AN: 23359

South Asian (SAS) AF: 0.528 AC: 17775 AN: 33655

European-Finnish (FIN) AF: 0.415 AC: 12035 AN: 28989

Middle Eastern (MID) AF: 0.631 AC: 1025 AN: 1625

European-Non Finnish (NFE) AF: 0.481 AC: 117401 AN: 244273

Other (OTH) AF: 0.490 AC: 10919 AN: 22278

GnomAD4 genome AF: 0.436 AC: 48254 AN: 110645 Hom.: 7707 Cov.: 23 AF XY: 0.431 AC XY: 14188 AN XY: 32923

African (AFR) AF: 0.334 AC: 10206 AN: 30522

American (AMR) AF: 0.498 AC: 5186 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 1605 AN: 2637

East Asian (EAS) AF: 0.441 AC: 1540 AN: 3494

South Asian (SAS) AF: 0.519 AC: 1356 AN: 2612

European-Finnish (FIN) AF: 0.430 AC: 2495 AN: 5800

Middle Eastern (MID) AF: 0.631 AC: 135 AN: 214

European-Non Finnish (NFE) AF: 0.471 AC: 24835 AN: 52771

Other (OTH) AF: 0.471 AC: 703 AN: 1494

Alfa AF: 0.448 Hom.: 4379

Bravo AF: 0.440

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.44
DANN	Benign	0.58
PhyloP100		0.58
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12009069; hg19: chrX-28807345;