Genetic Variant ATRX:p.Pro842Ala (chrX-77682732-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000489.6(ATRX):c.2524C>G(p.Pro842Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,732 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P842S) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.101

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11426285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6 link	c.2524C>G	p.Pro842Ala	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.2524C>G	p.Pro842Ala	missense_variant	Exon 9 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181529

AF XY:

0.00

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.12e-7

AC:

AN:

1096732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362580

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26351

American (AMR)

AF:

0.00

AC:

AN:

35151

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19364

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

53986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841805

Other (OTH)

AF:

0.00

AC:

AN:

46058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

3.0

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.026

.;.;T;T

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.67

T;.;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

-0.24

PhyloP100

-0.10

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.7

N;N;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.0080

D;D;.;.

Sift4G

Benign

0.91

T;T;T;.

Polyphen

0.20

B;.;.;.

Vest4

0.077

MutPred

0.15

Gain of helix (P = 0.0496);.;.;.;

MVP

0.60

MPC

0.024

ClinPred

0.082

GERP RS

-0.93

gMVP

0.15

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over