X-77697597-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104428679

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 -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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/Likely_benign. Clinvar id is 128495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.:

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

GnomAD2 exomes

AF:

0.00780

AC:

1425

AN:

182592

AF XY:

0.00425

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 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

African (AFR)

AF:

0.0996

AC:

2624

AN:

26351

American (AMR)

AF:

0.00438

AC:

154

AN:

35154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19352

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30160

South Asian (SAS)

AF:

0.000167

AC:

AN:

53960

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40437

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0000523

AC:

AN:

841252

Other (OTH)

AF:

0.00595

AC:

274

AN:

46033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

110

221

331

442

552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<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:

0.0277

AC:

3086

AN:

111556

Hom.:

109

Cov.:

AF XY:

0.0232

AC XY:

785

AN XY:

33806

show subpopulations

African (AFR)

AF:

0.0962

AC:

2953

AN:

30688

American (AMR)

AF:

0.00846

AC:

AN:

10514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.000373

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5920

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000207

AC:

AN:

53128

Other (OTH)

AF:

0.0199

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0140

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jun 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

DANN

Benign

0.51

PhyloP100

-1.8

Mutation Taster

=100/0

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