X-77681715-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):c.3541G>C(p.Val1181Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,205,564 control chromosomes in the GnomAD database, including 3 homozygotes. There are 519 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., 43 hem., cov: 22)

Exomes 𝑓: 0.0013 ( 3 hom. 476 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.798

Publications

5 publications found

Variant links:

COSMIC-nc: COSV64886220

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006064117).

BP6

Variant X-77681715-C-G is Benign according to our data. Variant chrX-77681715-C-G is described in ClinVar as Benign. ClinVar VariationId is 133659.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 = 0.00131 (146/111396) while in subpopulation NFE AF = 0.0014 (74/52942). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 43 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.3541G>C	p.Val1181Leu	missense_variant	Exon 9 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.3541G>C	p.Val1181Leu	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

146

AN:

111339

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000228

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:

0.0108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000666

GnomAD2 exomes

AF:

0.00149

AC:

266

AN:

178470

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.000113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00844

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.00129

AC:

1408

AN:

1094168

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

476

AN XY:

360358

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26146

American (AMR)

AF:

0.0000868

AC:

AN:

34556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19254

East Asian (EAS)

AF:

0.00

AC:

AN:

30138

South Asian (SAS)

AF:

0.000343

AC:

AN:

52514

European-Finnish (FIN)

AF:

0.00982

AC:

397

AN:

40411

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00113

AC:

950

AN:

841088

Other (OTH)

AF:

0.000849

AC:

AN:

45948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00131

AC:

146

AN:

111396

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

33614

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30788

American (AMR)

AF:

0.00

AC:

AN:

10488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2611

European-Finnish (FIN)

AF:

0.0108

AC:

AN:

5945

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

52942

Other (OTH)

AF:

0.000657

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000654

Hom.:

Bravo

AF:

0.000582

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00173

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00238

AC:

ExAC

AF:

0.00154

AC:

187

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Jul 13, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 22, 2016

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. -

ATRX-related disorder

Benign:1

Apr 04, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.6

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0068

.;.;T;T

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.76

T;.;T;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Benign

-0.61

PhyloP100

-0.80

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.53

N;N;.;.

REVEL

Benign

0.12

Sift

Uncertain

0.024

D;D;.;.

Sift4G

Benign

0.37

T;T;T;T

Polyphen

0.0070

B;.;.;.

Vest4

0.032

MVP

0.49

MPC

0.024

ClinPred

0.0012

GERP RS

-3.0

PromoterAI

-0.0084

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

gMVP

0.12

Mutation Taster

=99/1

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