X-77652291-TTCCTCC-TTCCTCCTCC

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000489.6(ATRX):c.4377_4379dupGGA(p.Glu1460dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,204,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000073 ( 0 hom. 0 hem. )

Consequence

ATRX
NM_000489.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:2

Conservation

PhyloP100: 0.241

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: Likely_benign. The variant received -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000489.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.4377_4379dupGGA	p.Glu1460dup	disruptive_inframe_insertion	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_4379dupGGA	p.Glu1460dup	disruptive_inframe_insertion	Exon 15 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.0000182

AC:

AN:

110026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000661

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000223

AC:

AN:

178979

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000230

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000731

AC:

AN:

1094408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360524

show subpopulations

African (AFR)

AF:

0.000228

AC:

AN:

26358

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19362

East Asian (EAS)

AF:

0.00

AC:

AN:

30184

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54061

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840147

Other (OTH)

AF:

0.00

AC:

AN:

46000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000182

AC:

AN:

110026

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32396

show subpopulations

African (AFR)

AF:

0.0000661

AC:

AN:

30253

American (AMR)

AF:

0.00

AC:

AN:

10256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2625

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5701

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52667

Other (OTH)

AF:

0.00

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

Nov 16, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame duplication of one amino acid in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24728327) -

GenomeConnect - Brain Gene Registry

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 11-23-2022 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Alpha thalassemia-X-linked intellectual disability syndrome

Uncertain:1

Sep 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.4377_4379dup, results in the insertion of 1 amino acid(s) to the ATRX protein (p.Glu1464dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ATRX-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.24

Splicing

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