X-77688844-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000489.6(ATRX):​c.568C>A​(p.Pro190Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P190A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

ATRX
NM_000489.6 missense

Scores

12
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60
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 was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000489.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-77688844-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11734.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATRXNM_000489.6 linkc.568C>A p.Pro190Thr missense_variant Exon 7 of 35 ENST00000373344.11 NP_000480.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATRXENST00000373344.11 linkc.568C>A p.Pro190Thr missense_variant Exon 7 of 35 1 NM_000489.6 ENSP00000362441.4 P46100-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1093840
Hom.:
0
Cov.:
29
AF XY:
0.00
AC XY:
0
AN XY:
359414
African (AFR)
AF:
0.00
AC:
0
AN:
26327
American (AMR)
AF:
0.00
AC:
0
AN:
35204
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19351
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54048
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40275
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4121
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
838391
Other (OTH)
AF:
0.00
AC:
0
AN:
45943
GnomAD4 genome
Cov.:
23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.66
D
BayesDel_noAF
Pathogenic
0.72
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.47
.;.;T;T;.;T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;.;D;D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
PhyloP100
9.6
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.4
D;D;.;.;.;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;.;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.79
MutPred
0.79
Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;
MVP
0.98
MPC
2.4
ClinPred
1.0
D
GERP RS
5.4
gMVP
0.99
Mutation Taster
=11/89
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs122445103; hg19: chrX-76944337; API