X-77683698-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000489.6(ATRX):​c.1558G>C​(p.Val520Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000894 in 111,795 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. 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. V520F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Consequence

ATRX
NM_000489.6 missense

Scores

4
7
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.68

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: 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38763577).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATRXNM_000489.6 linkc.1558G>C p.Val520Leu missense_variant Exon 9 of 35 ENST00000373344.11 NP_000480.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATRXENST00000373344.11 linkc.1558G>C p.Val520Leu missense_variant Exon 9 of 35 1 NM_000489.6 ENSP00000362441.4 P46100-1

Frequencies

GnomAD3 genomes
AF:
0.00000894
AC:
1
AN:
111795
Hom.:
0
Cov.:
22
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000894
AC:
1
AN:
111795
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33977
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30800
American (AMR)
AF:
0.00
AC:
0
AN:
10505
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2648
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3560
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2698
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6029
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
239
European-Non Finnish (NFE)
AF:
0.0000188
AC:
1
AN:
53133
Other (OTH)
AF:
0.00
AC:
0
AN:
1499
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Benign
-0.13
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.036
.;.;T;T;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;.;D;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Benign
0.39
T;T;T;T;T
MetaSVM
Pathogenic
0.92
D
PhyloP100
4.7
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.1
N;N;.;.;.
REVEL
Uncertain
0.48
Sift
Uncertain
0.024
D;D;.;.;.
Sift4G
Uncertain
0.025
D;D;T;.;T
Polyphen
0.99
D;.;.;.;.
Vest4
0.23
MutPred
0.053
Loss of glycosylation at S523 (P = 0.2064);.;.;Loss of glycosylation at S523 (P = 0.2064);.;
MVP
0.86
MPC
0.20
ClinPred
0.91
D
GERP RS
5.0
gMVP
0.23
Mutation Taster
=95/5
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1287383551; hg19: chrX-76939190; API