rs797045408

Positions:

• chrX-77684418-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000489.6(ATRX):​c.838T>C​(p.Cys280Arg) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C280Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.95

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 11 ACMG points.

• PM1: In a domain ADD (size 137) in uniprot entity ATRX_HUMAN there are 31 pathogenic changes around while only 4 benign (89%) in NM_000489.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-77684417-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976782.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.838T>C	p.Cys280Arg	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.838T>C	p.Cys280Arg	missense_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2015

- -

ATRX-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2023

The ATRX c.838T>C variant is predicted to result in the amino acid substitution p.Cys280Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Cys280Tyr) has been reported in the hemizygous state in an individual with X-linked intellectual disability-hypotonic facies syndrome (Hettiarachchi et al. 2019. PubMed ID: 31781420). At this time, the clinical significance of the c.838T>C (p.Cys280Arg) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.41	.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-6.7	D;D;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.91
MutPred		0.77		Loss of stability (P = 0.0584);.;.;Loss of stability (P = 0.0584);.;
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.99

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

Other links and lift over

dbSNP: rs797045408; hg19: chrX-76939910; COSMIC: COSV64877084; COSMIC: COSV64877084;