X-28789324-C-T

Variant names:

• chrX-28789324-C-T
• rs200878713
• NM_014271.4:c.-20C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.01
• 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 -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 VariationId is 368187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 19 XL gene

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.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_055086.1	X5DNQ7
	IL1RAPL1	NM_014271.4	MANE Select	c.-20C>T		5_prime_UTR	Exon 2 of 11	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.-20C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000368278.1	Q9NZN1-1
	IL1RAPL1	ENST00000378993.6	TSL:1 MANE Select	c.-20C>T		5_prime_UTR	Exon 2 of 11	ENSP00000368278.1	Q9NZN1-1

Frequencies

GnomAD3 genomes AF: 0.000779 AC: 87 AN: 111641 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000785 AC: 143 AN: 182217 AF XY: 0.000944

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 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

African (AFR) AF: 0.000199 AC: 5 AN: 25090

American (AMR) AF: 0.000741 AC: 26 AN: 35071

Ashkenazi Jewish (ASJ) AF: 0.000476 AC: 9 AN: 18890

East Asian (EAS) AF: 0.00 AC: 0 AN: 29838

South Asian (SAS) AF: 0.00118 AC: 62 AN: 52342

European-Finnish (FIN) AF: 0.000124 AC: 5 AN: 40353

Middle Eastern (MID) AF: 0.00436 AC: 17 AN: 3899

European-Non Finnish (NFE) AF: 0.00113 AC: 874 AN: 772435

Other (OTH) AF: 0.00108 AC: 47 AN: 43646

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

African (AFR) AF: 0.0000974 AC: 3 AN: 30802

American (AMR) AF: 0.00210 AC: 22 AN: 10470

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00113 AC: 3 AN: 2654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5949

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00109 AC: 58 AN: 53158

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.00109 Hom.: 8

Bravo AF: 0.00102

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, X-linked 21 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		2.0
Mutation Taster		=298/2	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: rs200878713; hg19: chrX-28807441; COSMIC: COSV100150718;