rs797045406

Positions:

• chrX-77635982-TTCTTCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_000489.6(ATRX):​c.4626_4631delTGAAGA​(p.Asp1542_Glu1543del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATRX NM_000489.6 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.65

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000489.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-77635982-TTCTTCA-T is Pathogenic according to our data. Variant chrX-77635982-TTCTTCA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210497.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.4626_4631delTGAAGA	p.Asp1542_Glu1543del	disruptive_inframe_deletion	16/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.4626_4631delTGAAGA	p.Asp1542_Glu1543del	disruptive_inframe_deletion	16/35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2023

In-frame deletion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21505078, 33176815, 11449489) -

ATRX-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2023

The ATRX c.4626_4631del6 variant is predicted to result in an in-frame deletion (p.Asp1542_Glu1543del). This variant has been reported in the hemizygous state in individuals with ATRX syndrome (Gibbons et al. 2000. PubMed ID: 11449489; Table S1, Mitson et al. 2011. PubMed ID: 21505078; Lin et al. 2020. PubMed ID: 33176815). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Alpha-thalassemia/intellectual disability syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 21, 2016

- -

Alpha thalassemia-X-linked intellectual disability syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this deletion results in lower mRNA and protein levels (PMID: 21505078). This variant has been observed in a family affected with moderate mental retardation, expressive language delay, HbH inclusions, and hypospodia (PMID: 11449489). This variant is also known as c.4832_4837del; p.1540_1541delDE in the literature. ClinVar contains an entry for this variant (Variation ID: 210497). This variant is not present in population databases (ExAC no frequency). This variant, c.4626_4631delTGAAGA, results in the deletion of 2 amino acids of the ATRX protein (p.Asp1542_Glu1543del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045406; hg19: chrX-76891473;