rs143621153

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_000489.6(ATRX):​c.3211G>A​(p.Gly1071Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,209,149 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000038 ( 0 hom. 12 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

16

Clinical Significance

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

Conservation

PhyloP100: 0.875
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATRX. . Gene score misZ 3.1025 (greater than the threshold 3.09). GenCC has associacion of gene with alpha thalassemia-X-linked intellectual disability syndrome, ATR-X-related syndrome, intellectual disability-hypotonic facies syndrome, X-linked, 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.050637454).
BP6
Variant X-77682045-C-T is Benign according to our data. Variant chrX-77682045-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465052.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High Hemizygotes in GnomAdExome4 at 12 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATRXNM_000489.6 linkuse as main transcriptc.3211G>A p.Gly1071Arg missense_variant 9/35 ENST00000373344.11 NP_000480.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATRXENST00000373344.11 linkuse as main transcriptc.3211G>A p.Gly1071Arg missense_variant 9/351 NM_000489.6 ENSP00000362441 P3P46100-1

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111485
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33703
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:
0.0000377
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
182843
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
67583
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000368
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
42
AN:
1097664
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
12
AN XY:
363120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000487
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111485
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33703
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000377
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Acquired hemoglobin H disease;C1845055:Alpha thalassemia-X-linked intellectual disability syndrome;C4759781:Intellectual disability-hypotonic facies syndrome, X-linked, 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
ATRX-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 20, 2024The ATRX c.3211G>A variant is predicted to result in the amino acid substitution p.Gly1071Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 11, 2016This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Alpha thalassemia-X-linked intellectual disability syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
14
DANN
Benign
0.82
DEOGEN2
Benign
0.015
.;.;T;T
FATHMM_MKL
Benign
0.33
N
LIST_S2
Benign
0.77
T;.;T;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.051
T;T;T;T
MetaSVM
Benign
-0.55
T
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.80
N;N;.;.
REVEL
Benign
0.28
Sift
Benign
0.85
T;T;.;.
Sift4G
Benign
0.52
T;T;T;T
Polyphen
0.0
B;.;.;.
Vest4
0.043
MutPred
0.098
Gain of solvent accessibility (P = 0.0097);.;.;.;
MVP
0.28
MPC
0.026
ClinPred
0.030
T
GERP RS
2.5
gMVP
0.068

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

LitVar

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

Other links and lift over

dbSNP: rs143621153; hg19: chrX-76937537; COSMIC: COSV64873246; COSMIC: COSV64873246; API