X-77698596-A-T

Variant names:

• chrX-77698596-A-T
• rs782553856
• ENST00000623321.3:c.2T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The ENST00000623321.3(ATRX):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATRX ENST00000623321.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 77698594. Lost 0.003 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRX	NM_000489.6	c.167T>A	p.Met56Lys	missense_variant	Exon 3 of 35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.167T>A	p.Met56Lys	missense_variant	Exon 3 of 35	1	NM_000489.6	ENSP00000362441.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 56 of the ATRX protein (p.Met56Lys). 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: 575515). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	.;.;T;T;.;T;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.72	T;.;T;T;D;D;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.025	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.24	N;N;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.16	T;T;.;.;.;.;.
Sift4G	Benign	0.29	T;T;T;.;D;D;.
Polyphen		0.26	B;.;.;.;.;.;.
Vest4		0.50
MutPred		0.24		Gain of ubiquitination at M56 (P = 0.009);Gain of ubiquitination at M56 (P = 0.009);Gain of ubiquitination at M56 (P = 0.009);Gain of ubiquitination at M56 (P = 0.009);.;.;.;
MVP		0.92
MPC		1.7
ClinPred		0.27	T
GERP RS		3.5
gMVP		0.12

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: rs782553856; hg19: chrX-76954084;