rs122445110

Positions:

• chrX-77589902-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The ENST00000373344.11(ATRX):​c.6149T>C​(p.Ile2050Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATRX ENST00000373344.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.81

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Helicase C-terminal (size 180) in uniprot entity ATRX_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in ENST00000373344.11
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant X-77589902-A-G is Pathogenic according to our data. Variant chrX-77589902-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11744.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRX	NM_000489.6	c.6149T>C	p.Ile2050Thr	missense_variant	27/35	ENST00000373344.11	NP_000480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRX	ENST00000373344.11	c.6149T>C	p.Ile2050Thr	missense_variant	27/35	1	NM_000489.6	ENSP00000362441	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2014

- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

History of neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.81
MutPred		0.89		Loss of stability (P = 0.0062);.;
MVP		1.0
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs122445110; hg19: chrX-76845372;