X-28789425-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_014271.4(IL1RAPL1):​c.82G>A​(p.Ala28Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,175,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000013 ( 0 hom. 7 hem. )

Consequence

IL1RAPL1
NM_014271.4 missense, splice_region

Scores

1
4
12
Splicing: ADA: 0.9999
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant X-28789425-G-A is Benign according to our data. Variant chrX-28789425-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2432844.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS2
High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IL1RAPL1NM_014271.4 linkc.82G>A p.Ala28Thr missense_variant, splice_region_variant Exon 2 of 11 ENST00000378993.6 NP_055086.1 Q9NZN1-1X5DNQ7
IL1RAPL1XM_017029240.2 linkc.82G>A p.Ala28Thr missense_variant, splice_region_variant Exon 2 of 11 XP_016884729.1 Q9NZN1-1X5DNQ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IL1RAPL1ENST00000378993.6 linkc.82G>A p.Ala28Thr missense_variant, splice_region_variant Exon 2 of 11 1 NM_014271.4 ENSP00000368278.1 Q9NZN1-1

Frequencies

GnomAD3 genomes
AF:
0.0000268
AC:
3
AN:
111760
Hom.:
0
Cov.:
23
AF XY:
0.0000295
AC XY:
1
AN XY:
33944
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000564
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183295
Hom.:
0
AF XY:
0.0000148
AC XY:
1
AN XY:
67773
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000244
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000132
AC:
14
AN:
1063800
Hom.:
0
Cov.:
26
AF XY:
0.0000210
AC XY:
7
AN XY:
332562
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000173
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000268
AC:
3
AN:
111760
Hom.:
0
Cov.:
23
AF XY:
0.0000295
AC XY:
1
AN XY:
33944
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000564
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000105
Hom.:
0
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Intellectual disability, X-linked 21 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 06, 2021- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.51
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.32
T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.4
L
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.59
N
REVEL
Benign
0.18
Sift
Benign
0.25
T
Sift4G
Benign
0.066
T
Polyphen
0.84
P
Vest4
0.32
MVP
0.66
MPC
0.86
ClinPred
0.23
T
GERP RS
5.8
Varity_R
0.33
gMVP
0.64

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.99
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs377167082; hg19: chrX-28807542; COSMIC: COSV56279012; API