rs148015780

Positions:

• chrX-77684410-G-A
• chrX-77684410-G-C
• chrX-77684410-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000489.6(ATRX):​c.846C>T​(p.Ser282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,209,247 control chromosomes in the GnomAD database, including 4 homozygotes. There are 517 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (3 hom. 491 hem.)
• Consequence: ATRX NM_000489.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.980

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=-0.82).
• BP6: Variant X-77684410-G-A is Benign according to our data. Variant chrX-77684410-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77684410-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (115/111979) while in subpopulation NFE AF= 0.00175 (93/53154). AF 95% confidence interval is 0.00146. There are 1 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.846C>T	p.Ser282=	synonymous_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.846C>T	p.Ser282=	synonymous_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 115 AN: 111927 Hom.: 1 Cov.: 23 AF XY: 0.000761 AC XY: 26 AN XY: 34169

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000556

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000808 AC: 148 AN: 183206 Hom.: 1 AF XY: 0.000900 AC XY: 61 AN XY: 67760

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.000157

Gnomad FIN exome AF: 0.000625

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00142 AC: 1558 AN: 1097268 Hom.: 3 Cov.: 32 AF XY: 0.00135 AC XY: 491 AN XY: 362662

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000331

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.000567

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00103 AC: 115 AN: 111979 Hom.: 1 Cov.: 23 AF XY: 0.000760 AC XY: 26 AN XY: 34231

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000558

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.00131 Hom.: 11

Bravo AF: 0.000842

EpiCase AF: 0.00104

EpiControl AF: 0.00124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2016	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2017

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.53

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: rs148015780; hg19: chrX-76939902;