X-77683431-G-C

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.1825C>G(p.Pro609Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,207,898 control chromosomes in the GnomAD database, including 3 homozygotes. There are 70 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P609S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., 10 hem., cov: 22)

Exomes 𝑓: 0.00019 ( 3 hom. 60 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.728

Publications

9 publications found

Variant links:

COSMIC-nc: COSV64872839

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=0.005873382).

BP6

Variant X-77683431-G-C is Benign according to our data. Variant chrX-77683431-G-C is described in ClinVar as Benign. ClinVar VariationId is 133654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00034 (38/111900) while in subpopulation EAS AF = 0.0101 (36/3565). AF 95% confidence interval is 0.0075. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.1825C>G	p.Pro609Ala	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.1825C>G	p.Pro609Ala	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4		P46100-1

Frequencies

GnomAD3 genomes

AF:

0.000340

AC:

AN:

111850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0101

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00111

AC:

204

AN:

183133

AF XY:

0.000827

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

205

AN:

1095998

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

AN XY:

361448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26353

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.00626

AC:

189

AN:

30190

South Asian (SAS)

AF:

0.0000925

AC:

AN:

54083

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

840116

Other (OTH)

AF:

0.000217

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000340

AC:

AN:

111900

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30892

American (AMR)

AF:

0.00

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.0101

AC:

AN:

3565

South Asian (SAS)

AF:

0.000372

AC:

AN:

2691

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6071

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53067

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000434

Hom.:

Bravo

AF:

0.000434

ExAC

AF:

0.000964

AC:

117

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1Other:1

May 11, 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.1825C>G (p.Pro609Ala) results in a non-conservative amino acid change in 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 0.0011 in 183133 control chromosomes, predominantly at a frequency of 0.014 within the East Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 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 East Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:1

Oct 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30359267) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.024

.;.;T;T

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.68

T;.;T;T

MetaRNN

Benign

0.0059

T;T;T;T

MetaSVM

Benign

-0.66

PhyloP100

0.73

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.65

N;N;.;.

REVEL

Benign

0.15

Sift

Uncertain

0.025

D;D;.;.

Sift4G

Benign

0.42

T;T;T;.

Polyphen

0.048

B;.;.;.

Vest4

0.044

MVP

0.59

MPC

0.024

ClinPred

0.013

GERP RS

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.12

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