X-77663378-T-G

Position:

chrX-77663378-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000489.6(ATRX):c.4120+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,208,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 191 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., 20 hem., cov: 23)

Exomes 𝑓: 0.00050 ( 0 hom. 171 hem. )

Consequence

ATRX
NM_000489.6 splice_region, intron

Scores

Splicing: ADA: 0.5305

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.230

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-77663378-T-G is Benign according to our data. Variant chrX-77663378-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193997.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000454 (51/112264) while in subpopulation NFE AF= 0.00062 (33/53241). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6 linkuse as main transcript	c.4120+4A>C		splice_region_variant, intron_variant		ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ATRX	ENST00000373344.11 linkuse as main transcript	c.4120+4A>C	splice_region_variant, intron_variant	1	NM_000489.6	ENSP00000362441.4	P46100-1
ATRX	ENST00000395603.7 linkuse as main transcript	c.4006+4A>C	splice_region_variant, intron_variant	1		ENSP00000378967.3	P46100-4
ATRX	ENST00000624166.3 linkuse as main transcript	c.3916+4A>C	splice_region_variant, intron_variant	1		ENSP00000485103.1	A0A096LNL9
ATRX	ENST00000480283.5 linkuse as main transcript	n.*3748+4A>C	splice_region_variant, intron_variant	1		ENSP00000480196.1	A0A087WWG0

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

112210

Hom.:

Cov.:

AF XY:

0.000582

AC XY:

AN XY:

34364

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:

0.00278

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000620

Gnomad OTH

AF:

0.000660

GnomAD3 exomes

AF:

0.000485

AC:

AN:

183354

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

67842

show subpopulations

Gnomad AFR exome

AF:

0.0000760

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:

0.00244

Gnomad NFE exome

AF:

0.000586

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000495

AC:

543

AN:

1096188

Hom.:

Cov.:

AF XY:

0.000473

AC XY:

171

AN XY:

361610

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00217

Gnomad4 NFE exome

AF:

0.000514

Gnomad4 OTH exome

AF:

0.000456

GnomAD4 genome

AF:

0.000454

AC:

AN:

112264

Hom.:

Cov.:

AF XY:

0.000581

AC XY:

AN XY:

34428

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:

0.00278

Gnomad4 NFE

AF:

0.000620

Gnomad4 OTH

AF:

0.000651

Alfa

AF:

0.0000727

Hom.:

Bravo

AF:

0.000261

EpiCase

AF:

0.000545

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 12, 2015

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.49

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over