NM_000489.6:c.1558G>T

Variant names:

• chrX-77683698-C-A
• rs1287383551
• NM_000489.6:c.1558G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000489.6(ATRX):​c.1558G>T​(p.Val520Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 4.68

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.410879).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.1558G>T	p.Val520Phe	missense_variant	Exon 9 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.1558G>T	p.Val520Phe	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 22

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neuroendocrine pancreatic tumor Other:1

Nov 13, 2024

Genome Sciences Centre, British Columbia Cancer Agency

Significance: -

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	.;.;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;T;T;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Pathogenic	0.96	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;N;.;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.089	T;T;.;.;.
Sift4G	Benign	0.10	T;T;D;.;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.50
MutPred		0.060		Loss of glycosylation at S519 (P = 0.1174);.;.;Loss of glycosylation at S519 (P = 0.1174);.;
MVP		0.82
MPC		0.22
ClinPred		0.88	D
GERP RS		5.0
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1287383551; hg19: chrX-76939190;