X-77683562-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000489.6(ATRX):​c.1694T>C​(p.Ile565Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

ATRX
NM_000489.6 missense

Scores

2
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.542
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.050482064).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATRXNM_000489.6 linkc.1694T>C p.Ile565Thr 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.1694T>C p.Ile565Thr missense_variant Exon 9 of 35 1 NM_000489.6 ENSP00000362441.4 P46100-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jun 06, 2014
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
0.82
DANN
Benign
0.28
DEOGEN2
Benign
0.0097
.;.;T;T;.
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.69
T;.;T;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.050
T;T;T;T;T
MetaSVM
Benign
-0.54
T
PrimateAI
Benign
0.37
T
PROVEAN
Benign
0.54
N;N;.;.;.
REVEL
Uncertain
0.29
Sift
Benign
0.52
T;T;.;.;.
Sift4G
Benign
0.39
T;T;T;.;T
Polyphen
0.0
B;.;.;.;.
Vest4
0.10
MutPred
0.12
Loss of stability (P = 0.0571);.;.;Loss of stability (P = 0.0571);.;
MVP
0.25
MPC
0.027
ClinPred
0.077
T
GERP RS
-1.9
gMVP
0.059

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1557140924; hg19: chrX-76939054; API