X-77682661-G-C

Position:

chrX-77682661-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):c.2595C>G(p.His865Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,206,879 control chromosomes in the GnomAD database, including 62 homozygotes. There are 4,081 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 4 hom., 236 hem., cov: 22)

Exomes 𝑓: 0.011 ( 58 hom. 3845 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 0.00300

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATRX. . Gene score misZ 3.1025 (greater than the threshold 3.09). GenCC has associacion of gene with alpha thalassemia-X-linked intellectual disability syndrome, ATR-X-related syndrome, intellectual disability-hypotonic facies syndrome, X-linked, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037919283).

BP6

Variant X-77682661-G-C is Benign according to our data. Variant chrX-77682661-G-C is described in ClinVar as [Benign]. Clinvar id is 93134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77682661-G-C is described in Lovd as [Likely_benign]. Variant chrX-77682661-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00811 (900/110984) while in subpopulation NFE AF= 0.0139 (733/52822). AF 95% confidence interval is 0.013. There are 4 homozygotes in gnomad4. There are 236 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6 linkuse as main transcript	c.2595C>G	p.His865Gln	missense_variant	9/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11 linkuse as main transcript	c.2595C>G	p.His865Gln	missense_variant	9/35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.00811

AC:

900

AN:

110934

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

236

AN XY:

33238

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00383

Gnomad ASJ

AF:

0.00379

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00974

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.0139

Gnomad OTH

AF:

0.00403

GnomAD3 exomes

AF:

0.00805

AC:

1456

AN:

180874

Hom.:

AF XY:

0.00798

AC XY:

530

AN XY:

66388

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00402

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00758

GnomAD4 exome

AF:

0.0109

AC:

11899

AN:

1095895

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

3845

AN XY:

362257

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00165

Gnomad4 ASJ exome

AF:

0.00392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.0128

Gnomad4 OTH exome

AF:

0.00890

GnomAD4 genome

AF:

0.00811

AC:

900

AN:

110984

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

236

AN XY:

33298

show subpopulations

Gnomad4 AFR

AF:

0.00160

Gnomad4 AMR

AF:

0.00383

Gnomad4 ASJ

AF:

0.00379

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00113

Gnomad4 FIN

AF:

0.00974

Gnomad4 NFE

AF:

0.0139

Gnomad4 OTH

AF:

0.00398

Alfa

AF:

0.0102

Hom.:

203

Bravo

AF:

0.00677

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.0144

AC:

ExAC

AF:

0.00860

AC:

1044

EpiCase

AF:

0.0112

EpiControl

AF:

0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30668521) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.11

DANN

Benign

0.43

DEOGEN2

Benign

0.0049

.;.;T;T

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.62

T;.;T;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.78

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.59

N;N;.;.

REVEL

Benign

0.15

Sift

Benign

0.92

T;T;.;.

Sift4G

Benign

0.59

T;T;T;.

Polyphen

0.0

B;.;.;.

Vest4

0.010

MutPred

0.13

Gain of MoRF binding (P = 0.0948);.;.;.;

MVP

0.20

MPC

0.024

ClinPred

0.00092

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.15

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