rs782646619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000489.6(ATRX):c.4366G>A(p.Glu1456Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,205,059 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1456E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.00014 ( 0 hom. 42 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.29

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1599378).

BS2

High Hemizygotes in GnomAdExome4 at 42 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.4366G>A	p.Glu1456Lys	missense	Exon 15 of 35	NP_000480.3
	ATRX	NM_138270.5		c.4252G>A	p.Glu1418Lys	missense	Exon 14 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.4366G>A	p.Glu1456Lys	missense	Exon 15 of 35	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7	TSL:1	c.4252G>A	p.Glu1418Lys	missense	Exon 14 of 34	ENSP00000378967.3	P46100-4
ATRX	ENST00000480283.5	TSL:1	n.*3994G>A		non_coding_transcript_exon	Exon 16 of 36	ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000330

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181365

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000137

AC:

150

AN:

1094535

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

360603

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26371

American (AMR)

AF:

0.0000284

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.00

AC:

AN:

54109

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.000176

AC:

148

AN:

840358

Other (OTH)

AF:

0.0000217

AC:

AN:

46008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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:

0.0000271

AC:

AN:

110524

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32738

show subpopulations

African (AFR)

AF:

0.0000330

AC:

AN:

30339

American (AMR)

AF:

0.00

AC:

AN:

10297

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5791

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52886

Other (OTH)

AF:

0.00

AC:

AN:

1476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000712

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alpha thalassemia-X-linked intellectual disability syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0040

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.42

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.052

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.55

PhyloP100

2.3

PrimateAI

Benign

0.46

PROVEAN

Benign

0.21

REVEL

Benign

0.20

Sift

Benign

0.098

Sift4G

Benign

0.41

Vest4

0.29

MutPred

0.38

Gain of methylation at E1456 (P = 0.014)

MVP

0.78

MPC

1.5

ClinPred

0.063

GERP RS

1.1

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.1

gMVP

0.23

Mutation Taster

=100/0

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