X-77688876-T-C

Position:

• chrX-77688876-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000373344.11(ATRX):​c.536A>G​(p.Asn179Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX ENST00000373344.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.67

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000373344.11
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATRX. . Gene score misZ 3.1025 (greater than the threshold 3.09). GenCC has associacion of gene with alpha thalassemia-X-linked intellectual disability syndrome, ATR-X-related syndrome, intellectual disability-hypotonic facies syndrome, X-linked, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant X-77688876-T-C is Pathogenic according to our data. Variant chrX-77688876-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77688876-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.536A>G	p.Asn179Ser	missense_variant	7/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.536A>G	p.Asn179Ser	missense_variant	7/35	1	NM_000489.6	ENSP00000362441	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093141, PMID:10995512). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16813605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.745>=0.6, SPLICEAI: 0.68). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2016	The c.536 A>G pathogenic variant in the ATRX gene has been reported previously in association with ATRX-related disorders (Picketts et al., 1996; Badens et al., 2006; Wada et al., 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies indicate that c.536 A>G creates a cryptic splice donor site, leading to a deletion of 63 nucleotides (reported as A751G using alternate nomenclature in Villard et al., 1997; reported as A869G using alternate nomenclature in Picketts et al., 1996). This substitution occurs in the ADD domain and pathogenic variants affecting this domain are presumed to have structural consequences on the ATRX protein and impact histone methylation (Argentaro et al., 2007; Iwase et al., 2011; Stenson et al., 2014). -

Intellectual disability-hypotonic facies syndrome, X-linked, 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 25, 2019	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The hemizygous p.Asn179Ser variant in ATRX was identified by our study in 3 siblings with x-linked mental retardation-hypotonic facies syndrome. This variant is assumed de novo in 1 individual, but maternity and paternity have not been confirmed (PMID: 16813605). The variant has been reported in at least 5 individuals of Japanese and unknown ethnicity with x-linked mental retardation-hypotonic facies syndrome (PMID: 16813605, 10995512, 8968741, 25252072, 33229608), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 93141) as pathogenic by GeneDx, HudsonAlpha Institute for Biotechnology, and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics. In vitro functional studies provide some evidence that the p.Asn179Ser variant may slightly impact protein function (PMID: 8968741). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in ATRX in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP2, PP3, PS4_supporting, PS3_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;T;T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.7	D;D;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.021	D;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;D
Polyphen		0.94	P;.;.;.;.;.
Vest4		0.90
MutPred		0.82		Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;.;
MVP		0.98
MPC		2.0
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123425; hg19: chrX-76944369; COSMIC: COSV64869634; COSMIC: COSV64869634;