rs45574238

Positions:

• chrX-77696659-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000489.6(ATRX):​c.288A>G​(p.Lys96=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00772 in 1,196,425 control chromosomes in the GnomAD database, including 556 homozygotes. There are 2,566 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (57 hom., 410 hem., cov: 23)
  • Exomes 𝑓: 0.0073 (499 hom. 2156 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.21

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-77696659-T-C is Benign according to our data. Variant chrX-77696659-T-C is described in ClinVar as [Benign]. Clinvar id is 93136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.288A>G	p.Lys96=	synonymous_variant	5/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.288A>G	p.Lys96=	synonymous_variant	5/35	1	NM_000489.6	ENSP00000362441	P3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1291 AN: 111851 Hom.: 54 Cov.: 23 AF XY: 0.0119 AC XY: 405 AN XY: 34085

Gnomad AFR AF: 0.00204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000553

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0295 AC: 5351 AN: 181126 Hom.: 417 AF XY: 0.0204 AC XY: 1347 AN XY: 65946

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.00732 AC: 7935 AN: 1084520 Hom.: 499 Cov.: 27 AF XY: 0.00612 AC XY: 2156 AN XY: 352286

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.0000333

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.0116 AC: 1298 AN: 111905 Hom.: 57 Cov.: 23 AF XY: 0.0120 AC XY: 410 AN XY: 34149

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000555

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00130

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.00791 Hom.: 57

Bravo AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2014	- -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.2
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs45574238; hg19: chrX-76952147; COSMIC: COSV64869694; COSMIC: COSV64869694;