rs782274478

Positions:

chrX-77522351-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000489.6(ATRX):c.6887A>G(p.Asn2296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,208,074 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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., 1 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.13

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.19641834).

BP6

Variant X-77522351-T-C is Benign according to our data. Variant chrX-77522351-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520624.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6 linkuse as main transcript	c.6887A>G	p.Asn2296Ser	missense_variant	32/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11 linkuse as main transcript	c.6887A>G	p.Asn2296Ser	missense_variant	32/35	1	NM_000489.6	ENSP00000362441	P3	P46100-1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111158

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33420

show subpopulations

Gnomad AFR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

183240

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67776

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:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1096916

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362570

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000131

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111158

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33420

show subpopulations

Gnomad4 AFR

AF:

0.0000654

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2015

- -

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 submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.89

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

D;.

M_CAP

Benign

0.067

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.0014

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.27

Sift

Benign

0.17

T;T

Sift4G

Benign

0.13

T;T

Vest4

0.27

MVP

0.90

MPC

1.1

ClinPred

0.037

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.45

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.

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