rs782386546

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000489.6(ATRX):c.3880G>C(p.Asp1294His) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,207,674 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts 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. D1294N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000099 ( 0 hom. 38 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.47

Publications

0 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: 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21644908).

BP6

Variant X-77664708-C-G is Benign according to our data. Variant chrX-77664708-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAdExome4 at 38 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.3880G>C	p.Asp1294His	missense	Exon 11 of 35	NP_000480.3
	ATRX	NM_138270.5		c.3766G>C	p.Asp1256His	missense	Exon 10 of 34	NP_612114.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATRX	ENST00000373344.11	TSL:1 MANE Select	c.3880G>C	p.Asp1294His	missense	Exon 11 of 35	ENSP00000362441.4
ATRX	ENST00000395603.7	TSL:1	c.3766G>C	p.Asp1256His	missense	Exon 10 of 34	ENSP00000378967.3
ATRX	ENST00000624166.3	TSL:1	c.3676G>C	p.Asp1226His	missense	Exon 11 of 14	ENSP00000485103.1

Frequencies

GnomAD3 genomes

AF:

0.0000898

AC:

AN:

111347

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000338

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000180

AC:

AN:

183118

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000693

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.0000735

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000994

AC:

109

AN:

1096327

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

361739

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26361

American (AMR)

AF:

0.000568

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30178

South Asian (SAS)

AF:

0.000333

AC:

AN:

54082

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40473

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.0000738

AC:

AN:

840501

Other (OTH)

AF:

0.000152

AC:

AN:

46035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.0000898

AC:

AN:

111347

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33551

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30657

American (AMR)

AF:

0.000576

AC:

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3577

South Asian (SAS)

AF:

0.00

AC:

AN:

2641

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

5913

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53079

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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:

0.000142

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

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 (1)

ATRX-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.057

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.22

MetaSVM

Pathogenic

0.86

PhyloP100

4.5

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.095

MVP

0.68

MPC

0.16

ClinPred

0.087

GERP RS

4.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

gMVP

0.12

Mutation Taster

=84/16

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

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