X-77682450-C-G

Variant names:

Variant summary

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

The NM_000489.6(ATRX):c.2806G>C(p.Val936Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,209,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V936F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000037 ( 0 hom. 8 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.501

Publications

2 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005138129).

BP6

Variant X-77682450-C-G is Benign according to our data. Variant chrX-77682450-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128496.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000108 (12/111566) while in subpopulation EAS AF = 0.00311 (11/3540). AF 95% confidence interval is 0.00174. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.2806G>C	p.Val936Leu	missense_variant	Exon 9 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11 link	c.2806G>C	p.Val936Leu	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111515

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:

0.00310

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000672

GnomAD2 exomes

AF:

0.000153

AC:

AN:

182709

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00202

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1097944

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00129

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841912

Other (OTH)

AF:

0.0000434

AC:

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000108

AC:

AN:

111566

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30796

American (AMR)

AF:

0.00

AC:

AN:

10492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00311

AC:

AN:

3540

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53075

Other (OTH)

AF:

0.000664

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000339

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 04, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

6.2

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.0088

.;.;T;T

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.88

D;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.0051

T;T;T;T

MetaSVM

Benign

-0.52

PhyloP100

0.50

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.38

N;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.46

T;T;.;.

Sift4G

Benign

0.30

T;T;T;.

Polyphen

0.0010

B;.;.;.

Vest4

0.039

MVP

0.49

MPC

0.024

ClinPred

0.014

GERP RS

3.0

PromoterAI

0.0019

Neutral

(source)

gMVP

0.083

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over