NM_000489.6:c.5579A>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.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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1860T) has been classified as Uncertain significance.

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

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

alpha thalassemia-X-linked intellectual disability syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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=0.019971818).

BP6

Variant X-77600552-T-C is Benign according to our data. Variant chrX-77600552-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11724.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 = 0.00648 (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 the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 222 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000489.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRX	NM_000489.6	MANE Select	c.5579A>G	p.Asn1860Ser	missense	Exon 23 of 35	NP_000480.3
	ATRX	NM_138270.5		c.5465A>G	p.Asn1822Ser	missense	Exon 22 of 34	NP_612114.2	P46100-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATRX	ENST00000373344.11	TSL:1 MANE Select	c.5579A>G	p.Asn1860Ser	missense	Exon 23 of 35	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7	TSL:1	c.5465A>G	p.Asn1822Ser	missense	Exon 22 of 34	ENSP00000378967.3	P46100-4
ATRX	ENST00000480283.5	TSL:1	n.*5207A>G		non_coding_transcript_exon	Exon 24 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

725

AN:

111843

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00651

AC:

1193

AN:

183291

AF XY:

0.00689

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 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

African (AFR)

AF:

0.00110

AC:

AN:

26362

American (AMR)

AF:

0.00108

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

220

AN:

19345

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30083

South Asian (SAS)

AF:

0.00307

AC:

166

AN:

54131

European-Finnish (FIN)

AF:

0.0107

AC:

434

AN:

40456

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0114

AC:

9565

AN:

841385

Other (OTH)

AF:

0.00847

AC:

390

AN:

46039

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

359

718

1076

1435

1794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.00648

AC:

725

AN:

111895

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

222

AN XY:

34077

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

30844

American (AMR)

AF:

0.00124

AC:

AN:

10517

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3573

South Asian (SAS)

AF:

0.00333

AC:

AN:

2705

European-Finnish (FIN)

AF:

0.0126

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00991

AC:

527

AN:

53153

Other (OTH)

AF:

0.00592

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

126

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:

0.00604

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Alpha thalassemia-X-linked intellectual disability syndrome (6)

not specified (7)

Astrocytoma, anaplastic (1)

Atypical teratoid rhabdoid tumor (1)

Inborn genetic diseases (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.9

(source)

DANN

Benign

0.78

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.62

PhyloP100

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.11

REVEL

Benign

0.23

Sift

Benign

1.0

Sift4G

Benign

0.82

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over