rs1557042387

Positions:

• chrX-77523307-T-A
• chrX-77523307-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000489.6(ATRX):​c.6794A>T​(p.Glu2265Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2265G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72

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 7 ACMG points.

• PM1: In a region_of_interest Interaction with MECP2 (size 270) in uniprot entity ATRX_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) 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-77523308-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2663846.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.6794A>T	p.Glu2265Val	missense_variant	31/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.6794A>T	p.Glu2265Val	missense_variant	31/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.93
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.62	D
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.014	D;D
Vest4		0.39
MutPred		0.33		Loss of solvent accessibility (P = 0.0703);.;
MVP		0.91
MPC		2.2
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-76778785; COSMIC: COSV105923617; COSMIC: COSV105923617;