rs1557142526

chrX-77684273-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000489.6(ATRX):c.983A>G(p.Glu328Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• 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: 5.95

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATRX

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.983A>G	p.Glu328Gly	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.983A>G	p.Glu328Gly	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

Sep 24, 2016

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces glutamic acid with glycine at codon 328 of the ATRX protein (p.Glu328Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 434470). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	24
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;.;T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N;.;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.025	D;D;.;.;.
Sift4G	Benign	0.15	T;T;T;.;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.36
MutPred		0.15		Loss of stability (P = 0.0494);.;.;Loss of stability (P = 0.0494);.;
MVP		0.87
MPC		0.053
ClinPred		0.94	D
GERP RS		5.4
gMVP		0.28

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: rs1557142526; hg19: chrX-76939765;