X-77652291-TTCCTCC-TTCC

Position:

chrX-77652291-TTCCTCC-TTCC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):c.4377_4379del(p.Glu1464del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 1.70

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

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

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 male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6 linkuse as main transcript	c.4377_4379del	p.Glu1464del	inframe_deletion	15/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11 linkuse as main transcript	c.4377_4379del	p.Glu1464del	inframe_deletion	15/35	1	NM_000489.6	P3	P46100-1
ATRX	ENST00000395603.7 linkuse as main transcript	c.4263_4265del	p.Glu1426del	inframe_deletion	14/34	1		A2	P46100-4
ATRX	ENST00000480283.5 linkuse as main transcript	c.4005_4007del		3_prime_UTR_variant, NMD_transcript_variant	16/36	1
ATRX	ENST00000623242.3 linkuse as main transcript			upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

159

AN:

110005

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

AN XY:

32391

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

GnomAD3 exomes

AF:

0.00156

AC:

279

AN:

178979

Hom.:

AF XY:

0.00146

AC XY:

AN XY:

65011

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 SAS exome

AF:

0.0000535

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

Gnomad4 AFR exome

AF:

0.000572

Gnomad4 AMR exome

AF:

0.000485

Gnomad4 ASJ exome

AF:

0.00135

Gnomad4 EAS exome

AF:

0.0000999

Gnomad4 SAS exome

AF:

0.000112

Gnomad4 FIN exome

AF:

0.00163

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00201

GnomAD4 genome

AF:

0.00144

AC:

159

AN:

110052

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

AN XY:

32448

show subpopulations

Gnomad4 AFR

AF:

0.000330

Gnomad4 AMR

AF:

0.00117

Gnomad4 ASJ

AF:

0.000381

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00136

Asia WGS

AF:

0.00279

AC:

AN:

2522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2013	- -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

ATRX-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over