X-77635906-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000489.6(ATRX):​c.4699+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000619 in 1,194,751 control chromosomes in the GnomAD database, including 1 homozygotes. There are 33 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 0.000054 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000063 ( 1 hom. 32 hem. )

Consequence

ATRX
NM_000489.6 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0150

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant X-77635906-G-A is Benign according to our data. Variant chrX-77635906-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000536 (6/111885) while in subpopulation SAS AF = 0.00149 (4/2688). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
BS2
High Hemizygotes in GnomAdExome4 at 32 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATRXNM_000489.6 linkc.4699+9C>T intron_variant Intron 16 of 34 ENST00000373344.11 NP_000480.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATRXENST00000373344.11 linkc.4699+9C>T intron_variant Intron 16 of 34 1 NM_000489.6 ENSP00000362441.4 P46100-1

Frequencies

GnomAD3 genomes
AF:
0.0000537
AC:
6
AN:
111830
Hom.:
0
Cov.:
22
show subpopulations
Gnomad AFR
AF:
0.0000651
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00148
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000877
AC:
15
AN:
170952
AF XY:
0.0000692
show subpopulations
Gnomad AFR exome
AF:
0.0000822
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000628
AC:
68
AN:
1082866
Hom.:
1
Cov.:
28
AF XY:
0.0000911
AC XY:
32
AN XY:
351440
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25990
American (AMR)
AF:
0.00
AC:
0
AN:
34701
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19057
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30108
South Asian (SAS)
AF:
0.00122
AC:
65
AN:
53094
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40203
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3132
European-Non Finnish (NFE)
AF:
0.00000241
AC:
2
AN:
831117
Other (OTH)
AF:
0.0000220
AC:
1
AN:
45464
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.474
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000536
AC:
6
AN:
111885
Hom.:
0
Cov.:
22
AF XY:
0.0000293
AC XY:
1
AN XY:
34083
show subpopulations
African (AFR)
AF:
0.0000650
AC:
2
AN:
30791
American (AMR)
AF:
0.00
AC:
0
AN:
10619
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2646
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3559
South Asian (SAS)
AF:
0.00149
AC:
4
AN:
2688
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
6004
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
215
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
53147
Other (OTH)
AF:
0.00
AC:
0
AN:
1531
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 26, 2017
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Alpha thalassemia-X-linked intellectual disability syndrome Benign:1
Feb 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: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
-0.59
CADD
Benign
7.5
DANN
Benign
0.78
PhyloP100
-0.015
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs782140505; hg19: chrX-76891397; API