X-77663471-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1

The NM_000489.6(ATRX):c.4031A>G(p.Lys1344Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,209,791 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K1344K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 2 hem. )

Consequence

ATRX
NM_000489.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.71

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 Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant where missense usually causes diseases, ATRX

BP4

Computational evidence support a benign effect (MetaRNN=0.18729776).

BP6

Variant X-77663471-T-C is Benign according to our data. Variant chrX-77663471-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434465.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000137 (15/1097501) while in subpopulation AMR AF= 0.000284 (10/35207). AF 95% confidence interval is 0.000154. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6 linkuse as main transcript	c.4031A>G	p.Lys1344Arg	missense_variant	12/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11 linkuse as main transcript	c.4031A>G	p.Lys1344Arg	missense_variant	12/35	1	NM_000489.6	P3	P46100-1
ATRX	ENST00000395603.7 linkuse as main transcript	c.3917A>G	p.Lys1306Arg	missense_variant	11/34	1		A2	P46100-4
ATRX	ENST00000624166.3 linkuse as main transcript	c.3827A>G	p.Lys1276Arg	missense_variant	12/14	1
ATRX	ENST00000480283.5 linkuse as main transcript	c.*3659A>G		3_prime_UTR_variant, NMD_transcript_variant	13/36	1

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34430

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

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:

0.0000600

AC:

AN:

183241

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67755

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000365

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:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1097501

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

362863

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000284

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:

0.00000238

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000949

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:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 04, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2016

- -

ATRX-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The ATRX c.4031A>G variant is predicted to result in the amino acid substitution p.Lys1344Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-76918960-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Alpha thalassemia-X-linked intellectual disability syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.30

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Uncertain

0.60

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;.

REVEL

Uncertain

0.43

Sift

Benign

0.051

T;T;.

Sift4G

Uncertain

0.043

D;T;T

Vest4

0.10

MutPred

0.20

Loss of ubiquitination at K1344 (P = 0.0087);.;.;

MVP

0.95

MPC

0.19

ClinPred

0.25

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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