rs122445108

Variant names:

• chrX-77717155-G-A
• rs122445108
• NM_000489.6:c.109C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000489.6(ATRX):​c.109C>T​(p.Arg37*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,244 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ATRX NM_000489.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 1.82
• Publications: 23 publications found

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]

ATRX Gene-Disease associations (from GenCC):

• alpha thalassemia-X-linked intellectual disability syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• ATR-X-related syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability-hypotonic facies syndrome, X-linked, 1

  Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-77717155-G-A is Pathogenic according to our data. Variant chrX-77717155-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.109C>T	p.Arg37*	stop_gained	Exon 2 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.109C>T	p.Arg37*	stop_gained	Exon 2 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094244 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360040

African (AFR) AF: 0.00 AC: 0 AN: 26310

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30146

South Asian (SAS) AF: 0.00 AC: 0 AN: 54000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838768

Other (OTH) AF: 0.00 AC: 0 AN: 45982

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome Pathogenic:4 Other:1

May 25, 2020

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_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with both X-linked dominant and recessive disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 35). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in more than 20 male patients with intellectual disability (ClinVar, PMID: 26350204, PMID: 24805811). (P) 0901 - Strong evidence for segregation with disease. The variant has been shown to segregate with disease in affected males in at least 5 families, with unaffected female carriers (PMID: 24805811). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Jan 22, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 26, 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.Arg37*) in the ATRX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATRX are known to be pathogenic (PMID: 15591283, 18409179, 23681356). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of alpha-thalassemia X-linked intellectual disability syndrome (PMID: 10632111, 15508018, 24805811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11742). Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on ATRX gene expression (PMID: 15508018, 15591283). For these reasons, this variant has been classified as Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability-hypotonic facies syndrome, X-linked, 1 Pathogenic:3

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation has been previously reported as disease-causing and was found once in our laboratory in an 8-year-old male with intellectual disability, hypotonia, dysmorphic features, GERD, febrile seizure, short stature, mirocephaly. -

Jun 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PP1 very strong -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011742.7). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Intellectual disability Pathogenic:2

Feb 13, 2019

Raymond Lab, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jul 25, 2014

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Dec 27, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R37* pathogenic mutation (also known as c.109C>T), located in coding exon 2 of the ATRX gene, results from a C to T substitution at nucleotide position 109. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been shown to segregate with disease in several large families with variable intellectual disability (mild to profound), speech impairment, facial anomalies including +/- hypertelorism, short philtrum, open mouth, full lower lip, and microcephaly, growth deficiency, hypotonia, +/- seizures, +/- urogenital anomalies, and decreased Hgb H inclusions compared to most ATRX probands (Basehore MJ et al. Clin. Genet., 2015 May;87:461-6, Guerrini, R et al. Ann. Neurol. 2000;47(1):117-21, Moncini, S et al. Meta Gene 2013;1:102-108). This mutation is often observed to result in a less severe phenotype than is typically observed in patients with nonsense mutations in the ATRX gene, (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Howard, MT et al. Med. Genet. 2004;41(12):951-6). Unaffected female carriers for this mutation have been observed to have highly skewed X-inactivation patterns of >90:10 (Abidi, FE et al. Eur. J. Hum. Genet. 2005;13(2):176-83, Basehore MJ et al. Clin. Genet., 2015 May;87:461-6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Acquired hemoglobin H disease;C1845055:Alpha thalassemia-X-linked intellectual disability syndrome;C4759781:Intellectual disability-hypotonic facies syndrome, X-linked, 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PS4_Moderate+PP1_Strong+PM6_Supporting -

not provided Pathogenic:1

Sep 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Segregates with X-linked intellectual disability, short stature, microcephaly, and dysmorphic features in multiple families; the heterozygous unaffected females showed skewed X-inactivation (Abidi et al., 2005; Basehore et al., 2015); Functional studies suggest that the variant may cause reduced protein expression compared to WT, however additional studies are needed to validate the impact of this variant on splicing (Howard et al., 2004); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32170002, 3239563, 25606380, 18409179, 25167861, 25326635, 20301622, 28293299, 33173999, 25679214, 26147798, 31685013, 29491882, 26997013, 20865721, 32277047, 26350204, 30231518, 36031702, 12953102, 28152038, 31452935, 24805811, 10632111, 15508018, 32901917, 15591283) -

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

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.53	D
PhyloP100		1.8
Vest4		0.82
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs122445108; hg19: chrX-76972632;