rs122445099

Variant names:

• chrX-77520832-G-A
• rs122445099
• NM_000489.6:c.7156C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000489.6(ATRX):​c.7156C>T​(p.Arg2386*) 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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX NM_000489.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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. Fraction of 0.0432 CDS is truncated, and there are 0 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 rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.7156C>T	p.Arg2386*	stop_gained	Exon 34 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.7156C>T	p.Arg2386*	stop_gained	Exon 34 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome Pathogenic:3

Mar 24, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATRX-related conditions. (I) 0108 - This gene is associated with both X-linked recessive and dominant disease. Carrier females may be asymptomatic, or affected with alpha-thalassaemia syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity and phenotypes have been observed among individuals with the same variant (PMID: 24805811, 23820649). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four downstream truncating variants have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability-hypotonic facies syndrome, X-linked, 1 Pathogenic:1

Oct 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in a similarly affected individual (PMID: 30190611). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23656349, 30190611, 30308447). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000363 /PMID: 7904209 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

ATRX-related disorder Pathogenic:1

Mar 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.87
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs122445099; hg19: chrX-76776310;