rs147331649

chrX-77656597-C-GchrX-77656597-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000489.6(ATRX):c.4177G>C(p.Val1393Leu) variant causes a missense 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: 22)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.20

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ATRX
• BP4: Computational evidence support a benign effect (MetaRNN=0.3031144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.4177G>C	p.Val1393Leu	missense_variant	13/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.4177G>C	p.Val1393Leu	missense_variant	13/35	1	NM_000489.6	P3
ATRX	ENST00000395603.7	c.4063G>C	p.Val1355Leu	missense_variant	12/34	1		A2
ATRX	ENST00000624166.3	c.3973G>C	p.Val1325Leu	missense_variant	13/14	1
ATRX	ENST00000480283.5	c.*3805G>C		3_prime_UTR_variant, NMD_transcript_variant	14/36	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182961 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67507

Gnomad AFR exome AF: 0.00

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alpha thalassemia-X-linked intellectual disability syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 16, 2017	This variant is not present in population databases (ExAC no frequency). In summary, this variant has uncertain impact on ATRX function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with an ATRX-related disease. This sequence change replaces valine with leucine at codon 1393 of the ATRX protein (p.Val1393Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	21
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.092	T;T;.
Sift4G	Benign	0.52	T;T;T
Vest4		0.19
MutPred		0.21		Loss of sheet (P = 0.0817);.;.;
MVP		0.91
MPC		1.6
ClinPred		0.43	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
gMVP		0.14

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: rs147331649; hg19: chrX-76912087;