rs122445099
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000489.6(ATRX):c.7156C>T(p.Arg2386Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2386R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
ATRX
NM_000489.6 stop_gained
NM_000489.6 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 3.90
Genes affected
ATRX (HGNC:886): (ATRX chromatin remodeler) The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-77520832-G-A is Pathogenic according to our data. Variant chrX-77520832-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77520832-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATRX | NM_000489.6 | c.7156C>T | p.Arg2386Ter | stop_gained | 34/35 | ENST00000373344.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATRX | ENST00000373344.11 | c.7156C>T | p.Arg2386Ter | stop_gained | 34/35 | 1 | NM_000489.6 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Alpha thalassemia-X-linked intellectual disability syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 24, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change creates a premature translational stop signal (p.Arg2386*) in the ATRX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 107 amino acid(s) of the ATRX protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with alpha-thalassemia X-linked intellectual disability syndrome (PMID: 7697714, 24690944, 28371217). It has also been observed to segregate with disease in related individuals. This variant is also known as C4635T (R1528*). ClinVar contains an entry for this variant (Variation ID: 11728). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 25, 2016 | - - |
Cryptorchidism;C0036857:Intellectual disability, severe;C0266362:Ambiguous genitalia;C0585442:Bone osteosarcoma;C4551563:Microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Intellectual disability-hypotonic facies syndrome, X-linked, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 24690944 , 28371217 , 7697714). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011728 / PMID: 7697714). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
ATRX-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2024 | The ATRX c.7156C>T variant is predicted to result in premature protein termination (p.Arg2386*). This variant has been reported in multiple individuals with X-linked intellectual disability syndrome (Gibbons et al 1995. PubMed ID: 7697714; Brett M et al 2014. PubMed ID: 24690944; Ji J et al 2017. PubMed ID: 28371217). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in ATRX are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at