NM_000489.6:c.2650G>A

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.2650G>A(p.Glu884Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,208,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 69 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. E884D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.00019 ( 0 hom. 69 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.16

Publications

5 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=0.016172469).

BP6

Variant X-77682606-C-T is Benign according to our data. Variant chrX-77682606-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000192 (211/1097123) while in subpopulation AMR AF = 0.000881 (31/35206). AF 95% confidence interval is 0.000637. There are 0 homozygotes in GnomAdExome4. There are 69 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 69 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.2650G>A	p.Glu884Lys	missense	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.2536G>A	p.Glu846Lys	missense	Exon 8 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.2650G>A	p.Glu884Lys	missense	Exon 9 of 35	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7	TSL:1	c.2536G>A	p.Glu846Lys	missense	Exon 8 of 34	ENSP00000378967.3	P46100-4
ATRX	ENST00000624166.3	TSL:1	c.2446G>A	p.Glu816Lys	missense	Exon 9 of 14	ENSP00000485103.1	A0A096LNL9

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

111552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000286

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000258

AC:

AN:

181912

AF XY:

0.000135

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.000192

AC:

211

AN:

1097123

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

AN XY:

362793

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.000881

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000204

AC:

172

AN:

841971

Other (OTH)

AF:

0.000174

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000126

AC:

AN:

111552

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33768

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30723

American (AMR)

AF:

0.000286

AC:

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

53039

Other (OTH)

AF:

0.00

AC:

AN:

1495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000217

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha thalassemia-X-linked intellectual disability syndrome (2)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.015

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.49

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.46

REVEL

Benign

0.13

Sift

Benign

0.26

Sift4G

Benign

0.73

Polyphen

0.0

Vest4

0.22

MVP

0.48

MPC

0.025

ClinPred

0.013

GERP RS

3.5

PromoterAI

0.0077

Neutral

(source)

gMVP

0.20

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over