dbSNP rs122445108: ATRX:p.Arg37* (chrX-77717155-G-A) – ACMG Classification: Pathogenic (18 pts)

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 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 11742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77717155-G-A is described in Lovd as [Pathogenic]. Variant chrX-77717155-G-A is described in Lovd as [Pathogenic]. Variant chrX-77717155-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	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 link	c.109C>T	p.Arg37*	stop_gained	Exon 2 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.14e-7

AC:

AN:

1094244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360040

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome

Pathogenic:3Other:1

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. -

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 01, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Pathogenic:3

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. -

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 -

Intellectual disability

Pathogenic:2

Jul 25, 2014

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2019

Raymond Lab, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

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

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.53

Vest4

0.82

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

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

rs122445108

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over