rs146863015

chrX-77683833-G-AchrX-77683833-G-CchrX-77683833-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000489.6(ATRX):c.1423C>T(p.His475Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,208,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H475D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: ATRX NM_000489.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.791

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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATRX
• BP4: Computational evidence support a benign effect (MetaRNN=0.12820587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRX	NM_000489.6	c.1423C>T	p.His475Tyr	missense_variant	9/35	ENST00000373344.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRX	ENST00000373344.11	c.1423C>T	p.His475Tyr	missense_variant	9/35	1	NM_000489.6	P3

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112097 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34295

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1096334 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 6 AN XY: 361808

Gnomad4 AFR exome AF: 0.00

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: 0.0000214

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112097 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34295

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability-hypotonic facies syndrome, X-linked, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Jan 13, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.38
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.13	T;.;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N;N;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.086	T;T;.;.;.
Sift4G	Uncertain	0.050	T;T;T;.;D
Polyphen		0.0020	B;.;.;.;.
Vest4		0.10
MutPred		0.16		Gain of phosphorylation at H475 (P = 8e-04);.;.;Gain of phosphorylation at H475 (P = 8e-04);.;
MVP		0.37
MPC		0.029
ClinPred		0.092	T
GERP RS		3.6
gMVP		0.077

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: rs146863015; hg19: chrX-76939325;