chrX-77697597-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000489.6(ATRX):c.228G>A(p.Ser76Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,208,385 control chromosomes in the GnomAD database, including 233 homozygotes. There are 1,550 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 0.028 ( 109 hom., 785 hem., cov: 23)

Exomes 𝑓: 0.0028 ( 124 hom. 765 hem. )

Consequence

ATRX
NM_000489.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.77

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant X-77697597-C-T is Benign according to our data. Variant chrX-77697597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77697597-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.77 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.228G>A	p.Ser76Ser	synonymous_variant	Exon 4 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.228G>A	p.Ser76Ser	synonymous_variant	Exon 4 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.0276

AC:

3081

AN:

111502

Hom.:

109

Cov.:

AF XY:

0.0232

AC XY:

783

AN XY:

33742

show subpopulations

Gnomad AFR

AF:

0.0963

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00848

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.00780

AC:

1425

AN:

182592

Hom.:

AF XY:

0.00425

AC XY:

285

AN XY:

67122

show subpopulations

Gnomad AFR exome

AF:

0.0995

Gnomad AMR exome

AF:

0.00348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000723

Gnomad SAS exome

AF:

0.0000533

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00284

AC:

3113

AN:

1096829

Hom.:

124

Cov.:

AF XY:

0.00211

AC XY:

765

AN XY:

362371

show subpopulations

Gnomad4 AFR exome

AF:

0.0996

Gnomad4 AMR exome

AF:

0.00438

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.000167

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.00595

GnomAD4 genome

AF:

0.0277

AC:

3086

AN:

111556

Hom.:

109

Cov.:

AF XY:

0.0232

AC XY:

785

AN XY:

33806

show subpopulations

Gnomad4 AFR

AF:

0.0962

Gnomad4 AMR

AF:

0.00846

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000373

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0140

Hom.:

Bravo

AF:

0.0318

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jun 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 13, 2014

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. -

Acquired hemoglobin H disease;C1845055:Alpha thalassemia-X-linked intellectual disability syndrome;C4759781:Intellectual disability-hypotonic facies syndrome, X-linked, 1

Benign:1

Sep 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.15

DANN

Benign

0.51

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