X-77652291-TTCCTCC-TTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):c.4377_4379delGGA(p.Glu1460del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,198,651 control chromosomes in the GnomAD database, including 2 homozygotes. There are 855 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., 48 hem., cov: 21)

Exomes 𝑓: 0.0023 ( 2 hom. 807 hem. )

Consequence

ATRX
NM_000489.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 1.70

Publications

8 publications found

Variant links:

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]

ATRX Gene-Disease associations (from GenCC):

alpha thalassemia-X-linked intellectual disability syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
ATR-X-related syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability-hypotonic facies syndrome, X-linked, 1
Inheritance: XL Classification: MODERATE Submitted by: Ambry Genetics

ATRX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000489.6

BP6

Variant X-77652291-TTCC-T is Benign according to our data. Variant chrX-77652291-TTCC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00144 (159/110052) while in subpopulation NFE AF = 0.00243 (128/52653). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.4377_4379delGGA	p.Glu1460del	disruptive_inframe_deletion	Exon 15 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11 link	c.4377_4379delGGA	p.Glu1460del	disruptive_inframe_deletion	Exon 15 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

159

AN:

110005

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00117

Gnomad ASJ

AF:

0.000381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00156

AC:

279

AN:

178979

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.000307

Gnomad AMR exome

AF:

0.000332

Gnomad ASJ exome

AF:

0.00162

Gnomad EAS exome

AF:

0.000146

Gnomad FIN exome

AF:

0.00328

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.00234

AC:

2544

AN:

1088599

Hom.:

AF XY:

0.00226

AC XY:

807

AN XY:

356721

show subpopulations

African (AFR)

AF:

0.000572

AC:

AN:

26233

American (AMR)

AF:

0.000485

AC:

AN:

35047

Ashkenazi Jewish (ASJ)

AF:

0.00135

AC:

AN:

19235

East Asian (EAS)

AF:

0.0000999

AC:

AN:

30018

South Asian (SAS)

AF:

0.000112

AC:

AN:

53580

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

38613

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00278

AC:

2322

AN:

836034

Other (OTH)

AF:

0.00201

AC:

AN:

45731

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00144

AC:

159

AN:

110052

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

AN XY:

32448

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

30314

American (AMR)

AF:

0.00117

AC:

AN:

10267

Ashkenazi Jewish (ASJ)

AF:

0.000381

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3522

South Asian (SAS)

AF:

0.00

AC:

AN:

2583

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

5690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00243

AC:

128

AN:

52653

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00182

Hom.:

Bravo

AF:

0.00136

Asia WGS

AF:

0.00279

AC:

AN:

2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 15, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATRX p.Glu1426del variant was not identified in the literature. The variant was identified in dbSNP (ID: rs398123423) and ClinVar (classified as likely benign by GeneDx and Invitae; classified as benign by Genetic Services Laboratory University of Chicago, EGL Genetic Diagnostics and Ambry Genetics). The variant was identified in control databases in 300 of 200007 chromosomes at a frequency of 0.0015 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 50 of 16081 chromosomes (freq: 0.003109), European (non-Finnish) in 217 of 91347 chromosomes (freq: 0.002376), Ashkenazi Jewish in 12 of 7581 chromosomes (freq: 0.001583), Other in 5 of 5218 chromosomes (freq: 0.000958), Latino in 9 of 27673 chromosomes (freq: 0.000325), African in 4 of 18738 chromosomes (freq: 0.000214), East Asian in 2 of 14663 chromosomes (freq: 0.000136), and South Asian in 1 of 18706 chromosomes (freq: 0.000053). This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codon 1426; the impact of this alteration on ATRX protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Mar 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 02, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATRX-related disorder

Benign:1

Jun 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=67/33

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over