NM_000489.6:c.3513A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000489.6(ATRX):c.3513A>T(p.Arg1171Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000916 in 1,200,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.99

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: 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25492662).

BP6

Variant X-77681743-T-A is Benign according to our data. Variant chrX-77681743-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434466.

BS2

High Hemizygotes in GnomAdExome4 at 2 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.3513A>T	p.Arg1171Ser	missense	Exon 9 of 35	NP_000480.3
	ATRX	NM_138270.5		c.3399A>T	p.Arg1133Ser	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.3513A>T	p.Arg1171Ser	missense	Exon 9 of 35	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7	TSL:1	c.3399A>T	p.Arg1133Ser	missense	Exon 8 of 34	ENSP00000378967.3	P46100-4
ATRX	ENST00000624166.3	TSL:1	c.3309A>T	p.Arg1103Ser	missense	Exon 9 of 14	ENSP00000485103.1	A0A096LNL9

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111487

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000668

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000574

AC:

AN:

174205

AF XY:

0.0000164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000392

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1089476

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

357488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25736

American (AMR)

AF:

0.0000300

AC:

AN:

33333

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19018

East Asian (EAS)

AF:

0.00

AC:

AN:

30135

South Asian (SAS)

AF:

0.00

AC:

AN:

51474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

839804

Other (OTH)

AF:

0.00

AC:

AN:

45710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000628

AC:

AN:

111487

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33683

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30743

American (AMR)

AF:

0.000668

AC:

AN:

10477

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53019

Other (OTH)

AF:

0.00

AC:

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.018

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.48

PhyloP100

2.0

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.25

Sift

Uncertain

0.0030

Sift4G

Benign

0.39

Polyphen

0.70

Vest4

0.25

MutPred

0.27

Gain of phosphorylation at R1171 (P = 0.0026)

MVP

0.75

MPC

0.025

ClinPred

0.55

GERP RS

5.7

PromoterAI

0.0076

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

gMVP

0.24

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over