chrX-77697597-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000489.6(ATRX):​c.228G>A​(p.Ser76Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,208,385 control chromosomes in the GnomAD database, including 233 homozygotes. There are 1,550 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 109 hom., 785 hem., cov: 23)
Exomes 𝑓: 0.0028 ( 124 hom. 765 hem. )

Consequence

ATRX
NM_000489.6 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.77
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 -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant X-77697597-C-T is Benign according to our data. Variant chrX-77697597-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77697597-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.77 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATRXNM_000489.6 linkc.228G>A p.Ser76Ser synonymous_variant Exon 4 of 35 ENST00000373344.11 NP_000480.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATRXENST00000373344.11 linkc.228G>A p.Ser76Ser synonymous_variant Exon 4 of 35 1 NM_000489.6 ENSP00000362441.4 P46100-1

Frequencies

GnomAD3 genomes
AF:
0.0276
AC:
3081
AN:
111502
Hom.:
109
Cov.:
23
AF XY:
0.0232
AC XY:
783
AN XY:
33742
show subpopulations
Gnomad AFR
AF:
0.0963
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00848
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000372
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00840
Gnomad NFE
AF:
0.000207
Gnomad OTH
AF:
0.0202
GnomAD3 exomes
AF:
0.00780
AC:
1425
AN:
182592
Hom.:
55
AF XY:
0.00425
AC XY:
285
AN XY:
67122
show subpopulations
Gnomad AFR exome
AF:
0.0995
Gnomad AMR exome
AF:
0.00348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000723
Gnomad SAS exome
AF:
0.0000533
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.00177
GnomAD4 exome
AF:
0.00284
AC:
3113
AN:
1096829
Hom.:
124
Cov.:
29
AF XY:
0.00211
AC XY:
765
AN XY:
362371
show subpopulations
Gnomad4 AFR exome
AF:
0.0996
Gnomad4 AMR exome
AF:
0.00438
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000332
Gnomad4 SAS exome
AF:
0.000167
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000523
Gnomad4 OTH exome
AF:
0.00595
GnomAD4 genome
AF:
0.0277
AC:
3086
AN:
111556
Hom.:
109
Cov.:
23
AF XY:
0.0232
AC XY:
785
AN XY:
33806
show subpopulations
Gnomad4 AFR
AF:
0.0962
Gnomad4 AMR
AF:
0.00846
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000373
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000207
Gnomad4 OTH
AF:
0.0199
Alfa
AF:
0.0140
Hom.:
65
Bravo
AF:
0.0318

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jun 19, 2014
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:2
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Dec 13, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Acquired hemoglobin H disease;C1845055:Alpha thalassemia-X-linked intellectual disability syndrome;C4759781:Intellectual disability-hypotonic facies syndrome, X-linked, 1 Benign:1
Sep 27, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
0.15
DANN
Benign
0.51

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: rs5959371; hg19: chrX-76953085; COSMIC: COSV104428679; COSMIC: COSV104428679; API