X-77600552-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):c.5579A>G(p.Asn1860Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,209,011 control chromosomes in the GnomAD database, including 46 homozygotes. There are 3,760 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 1 hom., 222 hem., cov: 22)

Exomes 𝑓: 0.0099 ( 45 hom. 3538 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:3B:20O:1

Conservation

PhyloP100: 1.03

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019971818).

BP6

Variant X-77600552-T-C is Benign according to our data. Variant chrX-77600552-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 11724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77600552-T-C is described in Lovd as [Likely_benign]. Variant chrX-77600552-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00648 (725/111895) while in subpopulation NFE AF= 0.00991 (527/53153). AF 95% confidence interval is 0.00921. There are 1 homozygotes in gnomad4. There are 222 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 222 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.5579A>G	p.Asn1860Ser	missense_variant	Exon 23 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.5579A>G	p.Asn1860Ser	missense_variant	Exon 23 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

725

AN:

111843

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

222

AN XY:

34015

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.0204

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.0117

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00991

Gnomad OTH

AF:

0.00600

GnomAD3 exomes

AF:

0.00651

AC:

1193

AN:

183291

Hom.:

AF XY:

0.00689

AC XY:

467

AN XY:

67821

show subpopulations

Gnomad AFR exome

AF:

0.000912

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00299

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00575

GnomAD4 exome

AF:

0.00989

AC:

10849

AN:

1097116

Hom.:

Cov.:

AF XY:

0.00975

AC XY:

3538

AN XY:

362770

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.00108

Gnomad4 ASJ exome

AF:

0.0114

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.00307

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0114

Gnomad4 OTH exome

AF:

0.00847

GnomAD4 genome

AF:

0.00648

AC:

725

AN:

111895

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

222

AN XY:

34077

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.0117

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.0126

Gnomad4 NFE

AF:

0.00991

Gnomad4 OTH

AF:

0.00592

Alfa

AF:

0.00808

Hom.:

Bravo

AF:

0.00556

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0111

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00967

AC:

ExAC

AF:

0.00645

AC:

783

EpiCase

AF:

0.00785

EpiControl

AF:

0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:3Benign:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Dec 19, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 23, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31019283, 28293299, 28492530, 8968741, 29602769, 18805826, 29304373, 24728327, 22995991, 24082139, 7697714) -

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

Significance: Likely benign

Review Status: no assertion criteria provided

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

- -

not specified

Benign:6Other:1

Jan 24, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATRX c.5579A>G (p.Asn1860Ser) results in a conservative amino acid change located in the SNF2, N-terminal domain (IPR000330) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0065 in 183291 control chromosomes, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATRX causing ATR-X Syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (n=8) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATRX p.Asn1822Ser variant was identified in the literature as a heterozygous variant in a mother and daughter with familial brain tumors; both patients also carried a TP53 variant known to cause Li Fraumeni syndrome (Nordfors_2018_PMID:29602769). The variant was also identified in 1 family with ATR-X syndrome, however the variant was suggested to have uncertain significance (Gibbons_1995_PMID:7697714). The variant was identified in dbSNP (ID: rs45439799) and ClinVar (classified as benign by Invitae, Ambry Genetics and three other clinical laboratories, classified as likely benign by Equipe Genetique des Anomalies du Developpement UniversitâˆšÂ© de Bourgogne, and classified as pathogenic by Tampere Brain Tumor Research Consortium University of Tampere). The variant was identified in control databases in 1371 of 205163 chromosomes (2 homozygous; 539 hemizygous) at a frequency of 0.006682 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 (non-Finnish) in 196 of 18551 chromosomes (freq: 0.01057), African in 947 of 92618 chromosomes (freq: 0.01022), Latino in 77 of 7663 chromosomes (freq: 0.01005), Ashkenazi Jewish in 37 of 5322 chromosomes (freq: 0.006952), South Asian in 57 of 19074 chromosomes (freq: 0.002988), European (Finnish) in 35 of 28028 chromosomes (freq: 0.001249) and Other in 22 of 19044 chromosomes (freq: 0.001155), but was not observed in the East Asian population. The p.Asn1822 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 this variant meets our laboratory's criteria to be classified as benign. -

Alpha thalassemia-X-linked intellectual disability syndrome

Pathogenic:1Benign:5

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely 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

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Astrocytoma, anaplastic

Pathogenic:1

Tampere Brain Tumor Research Consortium, University of Tampere

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Atypical teratoid rhabdoid tumor

Pathogenic:1

Tampere Brain Tumor Research Consortium, University of Tampere

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases

Benign:1

Jan 19, 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. -

Intellectual disability-hypotonic facies syndrome, X-linked, 1

Benign:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of intellectual disability-hypotonic facies syndrome, X-linked (MIM#309580), with 539 hemizygotes and 2 homozygotes in gnomAD v2. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.9

DANN

Benign

0.78

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.87

D;.

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.62

PrimateAI

Benign

0.32

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

0.82

T;T

Vest4

0.022

MVP

0.47

MPC

1.1

ClinPred

0.00061

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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