rs147331649
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_000489.6(ATRX):c.4177G>C(p.Val1393Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 22)
Consequence
ATRX
NM_000489.6 missense
NM_000489.6 missense
Scores
9
6
Clinical Significance
Conservation
PhyloP100: 2.20
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ATRX
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3031144).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATRX | NM_000489.6 | c.4177G>C | p.Val1393Leu | missense_variant | 13/35 | ENST00000373344.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATRX | ENST00000373344.11 | c.4177G>C | p.Val1393Leu | missense_variant | 13/35 | 1 | NM_000489.6 | P3 | |
ATRX | ENST00000395603.7 | c.4063G>C | p.Val1355Leu | missense_variant | 12/34 | 1 | A2 | ||
ATRX | ENST00000624166.3 | c.3973G>C | p.Val1325Leu | missense_variant | 13/14 | 1 | |||
ATRX | ENST00000480283.5 | c.*3805G>C | 3_prime_UTR_variant, NMD_transcript_variant | 14/36 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD3 exomes AF: 0.00000547 AC: 1AN: 182961Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67507
GnomAD3 exomes
AF:
AC:
1
AN:
182961
Hom.:
AF XY:
AC XY:
1
AN XY:
67507
Gnomad AFR exome
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Gnomad SAS exome
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GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Alpha thalassemia-X-linked intellectual disability syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 23, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2017 | This variant is not present in population databases (ExAC no frequency). In summary, this variant has uncertain impact on ATRX function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with an ATRX-related disease. This sequence change replaces valine with leucine at codon 1393 of the ATRX protein (p.Val1393Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Benign
T;T;.
Sift4G
Benign
T;T;T
Vest4
MutPred
Loss of sheet (P = 0.0817);.;.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at