rs587778085

Positions:

• chrX-77682743-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_000489.6(ATRX):​c.2513A>G​(p.Lys838Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,282 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 0.0000090 (0 hom., 1 hem., cov: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: -0.0400

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.15050173).
• BP6: Variant X-77682743-T-C is Benign according to our data. Variant chrX-77682743-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133648.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.2513A>G	p.Lys838Arg	missense_variant	9/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.2513A>G	p.Lys838Arg	missense_variant	9/35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111282 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33504

Gnomad AFR AF: 0.0000326

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

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111282 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33504

Gnomad4 AFR AF: 0.0000326

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.2513A>G (p.K838R) alteration is located in exon 9 (coding exon 9) of the ATRX gene. This alteration results from a A to G substitution at nucleotide position 2513, causing the lysine (K) at amino acid position 838 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Alpha thalassemia-X-linked intellectual disability syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 838 of the ATRX protein (p.Lys838Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATRX-related conditions. ClinVar contains an entry for this variant (Variation ID: 133648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATRX protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

ATRX: PP2, BS2 -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.5
DANN	Benign	0.73
DEOGEN2	Benign	0.017	.;.;T;T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	T;.;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.51	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.49	N;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.11	T;T;.;.
Sift4G	Benign	0.29	T;T;T;.
Polyphen		0.0040	B;.;.;.
Vest4		0.10
MutPred		0.14		Loss of methylation at K838 (P = 0.048);.;.;.;
MVP		0.74
MPC		0.022
ClinPred		0.064	T
GERP RS		1.2
gMVP		0.13

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

Other links and lift over

dbSNP: rs587778085; hg19: chrX-76938235;