rs200420513

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000489.6(ATRX):c.4120+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,208,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., 20 hem., cov: 23)

Exomes 𝑓: 0.00050 ( 0 hom. 171 hem. )

Consequence

ATRX
NM_000489.6 splice_region, intron

Scores

Splicing: ADA: 0.5305

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.230

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-77663378-T-G is Benign according to our data. Variant chrX-77663378-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193997.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000454 (51/112264) while in subpopulation NFE AF = 0.00062 (33/53241). AF 95% confidence interval is 0.000453. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 20 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.4120+4A>C		splice_region intron	N/A	NP_000480.3
	ATRX	NM_138270.5		c.4006+4A>C		splice_region intron	N/A	NP_612114.2	P46100-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATRX	ENST00000373344.11	TSL:1 MANE Select	c.4120+4A>C	splice_region intron	N/A	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7	TSL:1	c.4006+4A>C	splice_region intron	N/A	ENSP00000378967.3	P46100-4
ATRX	ENST00000624166.3	TSL:1	c.3916+4A>C	splice_region intron	N/A	ENSP00000485103.1	A0A096LNL9

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

112210

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00278

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000620

Gnomad OTH

AF:

0.000660

GnomAD2 exomes

AF:

0.000485

AC:

AN:

183354

AF XY:

0.000516

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00244

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000495

AC:

543

AN:

1096188

Hom.:

Cov.:

AF XY:

0.000473

AC XY:

171

AN XY:

361610

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26363

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54094

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

40496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.000514

AC:

432

AN:

840330

Other (OTH)

AF:

0.000456

AC:

AN:

46037

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000454

AC:

AN:

112264

Hom.:

Cov.:

AF XY:

0.000581

AC XY:

AN XY:

34428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31000

American (AMR)

AF:

0.00

AC:

AN:

10569

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2708

European-Finnish (FIN)

AF:

0.00278

AC:

AN:

6117

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000620

AC:

AN:

53241

Other (OTH)

AF:

0.000651

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000727

Hom.:

Bravo

AF:

0.000261

EpiCase

AF:

0.000545

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.49

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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